Ionic-resolution protoacoustic microscopy: A feasibility study.

Visualizing micro- and nano-scale biological entities requires high-resolution imaging and is conventionally achieved via optical microscopic techniques. Optical diffraction limits their resolution to ∼200 nm. This limit can be overcome by using ions with ∼1 MeV energy. Such ions penetrate through several micrometers in tissues, and their much shorter de Broglie wavelengths indicate that these ion beams can be focused to much shorter scales and hence can potentially facilitate higher resolution as compared to the optical techniques. Proton microscopy with ∼1 MeV protons has been shown to have reasonable inherent contrast between sub-cellular organelles. However, being a transmission-based modality, it is unsuitable for in vivo studies and cannot facilitate three-dimensional imaging from a single raster scan. Here, we propose proton-induced acoustic microscopy (PrAM), a technique based on pulsed proton irradiation and proton-induced acoustic signal collection. This technique is capable of label-free, super-resolution, 3D imaging with a single raster scan. Converting radiation energy into ultrasound enables PrAM with reflection mode detection, making it suitable for in vivo imaging and probing deeper than proton scanning transmission ion microscopy (STIM). Using a proton STIM image of HeLa cells, a coupled Monte Carlo+k-wave simulations-based feasibility study has been performed to demonstrate the capabilities of PrAM. We demonstrate that sub-50 nm lateral (depending upon the beam size and energy) and sub-micron axial resolution (based on acoustic detection bandwidth and proton beam pulse width) can be obtained using the proposed modality. By enabling visualization of biological phenomena at cellular and subcellular levels, this high-resolution microscopic technique enhances understanding of intricate cellular processes.

Model-Based 3-D X-Ray Induced Acoustic Computerized Tomography.

X-ray-induced acoustic (XA) computerized tomography (XACT) is an evolving imaging technique that aims to reconstruct the X-ray energy deposition from XA measurements. Main challenges in XACT are the poor signal-to-noise ratio and limited field-of-view, which cause artifacts in the images. We demonstrate the efficacy of model-based (MB) algorithms for three-dimensional XACT and compare with the traditional algorithms. The MB algorithm is based on iterative, matrix-free approach for regularized-least-squares minimization corresponding to XACT. The matrix-free-LSQR (MF-LSQR) and the non-iterative model-backprojection (MBP) reconstructions were evaluated and compared with universal backprojection (UBP), time-reversal (TR) and fast-Fourier transform (FFT)-based reconstructions for numerical and experimental XACT datasets. The results demonstrate the capability of MF-LSQR algorithm to reduce noisy artifacts thus yielding better reconstructions. MBP and MF-LSQR algorithms perform particularly well with the experimental XACT dataset, where noise in signals significantly affects the reconstruction of the target in UBP and FFT-based reconstructions. The TR reconstruction for experimental XACT are comparable to MF-LSQR, but takes thrice as much time and filters the frequency components greater than maximum frequency supported by the grid, resulting loss of resolution. The MB algorithms are able to overcome the challenges in XACT and hence are vital for the clinical translation of XACT.

Simulation study of protoacoustics as a real-time in-line dosimetry tool for FLASH proton therapy.

BACKGROUND: Applying ultra-high dose rates to radiation therapy, otherwise known as FLASH, has been shown to be just as effective while sparing more normal tissue compared to conventional radiation therapy. However, there is a need for a dosimeter that is able to detect such high instantaneous dose, particularly in vivo. To fulfill this need, protoacoustics is introduced, which is an in vivo range verification method with submillimeter accuracy. PURPOSE: The purpose of this work is to demonstrate the feasibility of using protoacoustics as a method of in vivo real-time monitoring during FLASH proton therapy and investigating the resulting protoacoustic signal when dose per pulse and pulsewidth are varied through multiple simulation studies. METHODS: The dose distribution of a proton pencil beam was calculated through a Monte Carlo toolbox, TOPAS. Next, the k-Wave toolbox in MATLAB was used for performing protoacoustic simulations, where the initial proton dose deposition was inputted to model acoustic propagations, which were also used for reconstructions. Simulations involving the manipulation of the dose per pulse and pulsewidth were performed, and the temporal and spatial resolution for protoacoustic reconstructions were investigated as well. A 3D reconstruction was performed with a multiple beam spot profile to investigate the spatial resolution as well as determine the feasibility of 3D imaging with protoacoustics. RESULTS: Our results showed consistent linearity in the increasing dose-per-pulse, even up to rates considered for FLASH. The simulations and reconstructions were performed for a range of pulsewidths from 0.1 to 10 µs. The results show the characteristics of the proton beam after convolving the protoacoustic signal with the varying pulsewidths. 3D reconstruction was successfully performed with each beam being distinguishable using an 8 cm × 8 cm planar array. These simulation results show that measurements using protoacoustics has the potential for in vivo dosimetry in FLASH therapy during patient treatments in real time. CONCLUSION: Through this simulation study, the use of protoacoustics in FLASH therapy was verified and explored through observations of varying parameters, such as the dose per pulse and pulsewidth. 2D and 3D reconstructions were also completed. This study shows the significance of using protoacoustics and provides necessary information, which can further be explored in clinical settings.

Single-Pulse X-ray Acoustic Computed Tomographic Imaging for Precision Radiation Therapy.

Purpose: High-precision radiation therapy is crucial for cancer treatment. Currently, the delivered dose can only be verified via simulations with phantoms, and an in-tumor, online dose verification is still unavailable. An innovative detection method called x-ray-induced acoustic computed tomography (XACT) has recently shown the potential for imaging the delivered radiation dose within the tumor. Prior XACT imaging systems have required tens to hundreds of signal averages to achieve high-quality dose images within the patient, which reduces its real-time capability. Here, we demonstrate that XACT dose images can be reproduced from a single x-ray pulse (4 µs) with sub-mGy sensitivity from a clinical linear accelerator. Methods and Materials: By immersing an acoustic transducer in a homogeneous medium, it is possible to detect pressure waves generated by the pulsed radiation from a clinical linear accelerator. After rotating the collimator, signals of different angles are obtained to perform a tomographic reconstruction of the dose field. Using 2-stage amplification with further bandpass filtering increases the signal-to-noise ratio (SNR). Results: Acoustic peak SNR and voltage values were recorded for singular and dual-amplifying stages. The SNR for single-pulse mode was able to satisfy the Rose criterion, and the collected signals were able to reconstruct 2-dimensional images from the 2 homogeneous media. Conclusions: By overcoming the low SNR and requirement of signal averaging, single-pulse XACT imaging holds great potential for personalized dose monitoring from each individual pulse during radiation therapy.

Towards quantitative in vivo dosimetry using x-ray acoustic computed tomography.

BACKGROUND: Radiation dosimetry is essential for radiation therapy (RT) to ensure that radiation dose is accurately delivered to the tumor. Despite its wide use in clinical intervention, the delivered radiation dose can only be planned and verified via simulation. This makes precision radiotherapy challenging while in-line verification of the delivered dose is still absent in the clinic. X-ray-induced acoustic computed tomography (XACT) has recently been proposed as an imaging tool for in vivo dosimetry. PURPOSE: Most of the XACT studies focus on localizing the radiation beam. However, it has not been studied for its potential for quantitative dosimetry. The aim of this study was to investigate the feasibility of using XACT for quantitative in vivo dose reconstruction during radiotherapy. METHODS: Varian Eclipse system was used to generate simulated uniform and wedged 3D radiation field with a size of 4 cm × $ \times \ $ 4 cm. In order to use XACT for quantitative dosimetry measurements, we have deconvoluted the effects of both the x-ray pulse shape and the finite frequency response of the ultrasound detector. We developed a model-based image reconstruction algorithm to quantify radiation dose in vivo using XACT imaging, and universal back-projection (UBP) reconstruction is used as comparison. The reconstructed dose was calibrated before comparing it to the percent depth dose (PDD) profile. Structural similarity index matrix (SSIM) and root mean squared error (RMSE) are used for numeric evaluation. Experimental signals were acquired from 4 cm × $ \times \ $ 4 cm radiation field created by Linear Accelerator (LINAC) at depths of 6, 8, and 10 cm beneath the water surface. The acquired signals were processed before reconstruction to achieve accurate results. RESULTS: Applying model-based reconstruction algorithm with non-negative constraints successfully reconstructed accurate radiation dose in 3D simulation study. The reconstructed dose matches well with the PDD profile after calibration in experiments. The SSIMs between the model-based reconstructions and initial doses are over 85%, and the RMSEs of model-based reconstructions are eight times lower than the UBP reconstructions. We have also shown that XACT images can be displayed as pseudo-color maps of acoustic intensity, which correspond to different radiation doses in the clinic. CONCLUSION: Our results show that the XACT imaging by model-based reconstruction algorithm is considerably more accurate than the dose reconstructed by UBP algorithm. With proper calibration, XACT is potentially applicable to the clinic for quantitative in vivo dosimetry across a wide range of radiation modalities. In addition, XACT's capability of real-time, volumetric dose imaging seems well-suited for the emerging field of ultrahigh dose rate "FLASH" radiotherapy.

Single pulse protoacoustic range verification using a clinical synchrocyclotron.

Objective.Proton therapy as the next generation radiation-based cancer therapy offers dominant advantages over conventional radiation therapy due to the utilization of the Bragg peak; however, range uncertainty in beam delivery substantially mitigates the advantages of proton therapy. This work reports using protoacoustic measurements to determine the location of proton Bragg peak deposition within a water phantom in real time during beam delivery.Approach.In protoacoustics, proton beams have a definitive range, depositing a majority of the dose at the Bragg peak; this dose is then converted to heat. The resulting thermoelastic expansion generates a 3D acoustic wave, which can be detected by acoustic detectors to localize the Bragg peak.Main results.Protoacoustic measurements were performed with a synchrocyclotron proton machine over the exhaustive energy range from 45.5 to 227.15 MeV in clinic. It was found that the amplitude of the acoustic waves is proportional to proton dose deposition, and therefore encodes dosimetric information. With the guidance of protoacoustics, each individual proton beam (7 pC/pulse) can be directly visualized with sub-millimeter (<0.7 mm) resolution using single beam pulse for the first time.Significance.The ability to localize the Bragg peak in real-time and obtain acoustic signals proportional to dose within tumors could enable precision proton therapy and hope to progress towardsin vivomeasurements.

Ring artifacts removal in X-ray-induced acoustic computed tomography.

X-ray-induced acoustic computed tomography (XACT) is a hybrid imaging modality for detecting X-ray absorption distribution via ultrasound emission. It facilitates imaging from a single projection X-ray illumination, thus reducing the radiation exposure and improving imaging speed. Nonuniform detector response caused by the interference between multichannel data acquisition for ring array transducers and amplifier systems yields ring artifacts in the reconstructed XACT images, which compromises the image quality. We propose model-based algorithms for ring artifacts corrected XACT imaging and demonstrate their efficacy on numerical and experimental measurements. The corrected reconstructions indicate significantly reduced ring artifacts as compared to their conventional counterparts.

X-ray-induced acoustic computed tomography (XACT) imaging with single-shot nanosecond x-ray.

X-ray-induced acoustic computed tomography (XACT) has emerged as a promising imaging modality with broad applications in both biomedicine and nondestructive testing. The previous XACT imaging systems require thousands of averages to achieve reasonable images. Here, we report the experimental demonstration of single-shot XACT imaging of a metal object using a single-shot 50 ns x-ray pulse. A two-stage dedicated amplification and a 128-channel parallel data acquisition configuration were introduced for XACT imaging to enable sufficient acoustic signal amplification and maintain an overall low noise level for single-shot XACT imaging. Details of the system design are presented; the improved signal-to-noise ratio (>23 dB) and image reconstruction have been demonstrated with a ring ultrasound transducer array imaging system. The study paves the way for realizing real-time XACT imaging and its potential applications in image-guided intervention.

Model-Based X-Ray-Induced Acoustic Computed Tomography.

X-ray-induced acoustic computed tomography (XACT) provides X-ray absorption-based contrast with acoustic detection. For its clinical translation, XACT imaging often has a limited field of view. This can result in image artifacts and overall loss of quantification accuracy. In this article, we aim to demonstrate model-based XACT image reconstruction to address these problems. An efficient matrix-free implementation of the regularized LSQR (MF-LSQR)-based minimization scheme and a noniterative model back-projection (MBP) scheme for computing XACT reconstructions have been demonstrated in this article. The proposed algorithms have been numerically validated and then used to perform reconstructions from experimental measurements obtained from an XACT setup. While the commonly used back-projection (BP) algorithm produces limited-view and noisy artifacts in the region of interest (ROI), model-based LSQR minimization overcomes these issues. The model-based algorithms also reduce the ring artifacts caused due to the nonuniformity response of the multichannel data acquisition. Using the model-based reconstruction algorithms, we are able to obtain reasonable XACT reconstructions for acoustic measurements of up to 120° view. Although the MBP is more efficient than the model-based LSQR algorithm, it provides only the structural information of the ROI. Overall, it has been demonstrated that the model-based image reconstruction yields better image quality for XACT than the standard BP. Moreover, the combination of model-based image reconstruction with different regularization methods can solve the limited-view problem for XACT imaging (in many realistic cases where the full-view dataset is unavailable), and hence pave the way for future clinical translation.

One-step fluorescence photoacoustic tomography with the optical radiative transfer model.

We present adjoint-based Jacobian as well as gradient evaluations and corresponding reconstruction schemes to solve the fully nonlinear, optical radiative transfer modeled one-step fluorescence photoacoustic tomographic (FPAT) problem, which aims to reconstruct the map of absorption coefficient of the exogenous fluorophore from boundary photoacoustic data. The radiative transport equation (RTE) and frequency-domain photoacoustic equation have been employed to model light and photoacoustic wave propagation, respectively. Levenberg-Marquardt and Broyden-Fletcher-Goldfarb-Shanno reconstruction schemes have been used corresponding to the evaluated Jacobians and gradients, respectively. Numerical reconstructions obtained from the two schemes have been validated for scattering-dominant as well as nonscattering-dominant media in 2D. To the best of our knowledge, these are the first one-step FPAT reconstruction results in literature based on the optical RTE model.

Gradient-based one-step fluorescence photoacoustic tomography.

We propose a gradient-based scheme to solve the fluorescence photoacoustic tomographic (FPAT) problem in a fully nonlinear one-step setting, which aims to reconstruct the map of the absorption coefficient of an exogenous fluorophore from boundary photoacoustic pressure data. Adjoint-based gradient evaluation is presented for the FPAT problem in a frequency-domain photoacoustic equation setting. Numerical validations of the resulting Broyden-Fletcher-Goldfarb-Shanno (BFGS) reconstruction scheme are carried out in two dimensions for full- as well as limited-data test cases, and the results are compared with existing Jacobian-based one-step FPAT reconstructions. The reasonably comparable results of the one-step gradient- and Jacobian-based FPAT reconstruction schemes, coupled with the significant computational savings of the former, potentially set up the one-step gradient-based schemes as an advantageous method of choice for FPAT reconstructions. Further reconstruction studies carried out using quantitative photoacoustic tomography (QPAT)-based chromophore reconstructions as inputs to the FPAT inversions show a robustness of fluorophore absorption coefficient reconstructions to the QPAT-obtained inputs.

Comparative study of one-step and two-step quantitative fluorescence photoacoustic tomography.

Fluorescence optical tomography (FOT) is a well-known imaging technique, where fluorescent biological markers are injected to tag targeted tissues (tumors, proteins), and the absorption coefficient of fluorophore is reconstructed to provide contrast-enhanced images. Conventional FOT is known to have lack of stability to noise and shallow imaging depth due to strong optical scattering in biological tissue. Photoacoustic tomography (PAT) has been previously proposed to combine with FOT to resolve this issue. We propose a fully nonlinear one-step reconstruction in a diffuse-approximation modeled fluorescence photoacoustic tomographic (FPAT) setting, where the absorption coefficient of exogenous fluorophore is recovered directly from the photoacoustic data. Computational validations in two dimensions in single- and dual-grid reconstruction settings using full as well as partial data have been provided in support of the proposed algorithm. One-step schemes are particularly useful with respect to dual representations of field (optical and pressure) variables and optical parameters, especially in limited-data settings, which effectively help in constraining the optimization search space. We have compared the results of one- and two-step FPAT schemes and concluded that the one-step reconstructions are superior as compared with the corresponding two-step reconstructions. To the best of our knowledge, these are the first comparisons of one-step and two-step reconstructions in FPAT.