Gold nanoparticle-mediated photothermal therapy guidance with multi-wavelength photomagnetic imaging.

Difficulty in heating tumors with high spatial selectivity while protecting surrounding healthy tissues from thermal harm is a challenge for cancer photothermal treatment (PTT). To mitigate this problem, PTT mediated by photothermal agents (PTAs) has been established as a potential therapeutic technique to boost selectivity and reduce damage to surrounding healthy tissues. Various gold nanoparticles (AuNP) have been effectively utilized as PTAs, mainly using strategies to target cancerous tissue and increase selective thermal damage. Meanwhile, imaging can be used in tandem to monitor the AuNP distribution and guide the PTT. Mainly, the parameters impacting the induced temperature can be determined using simulation tools before treatment for effective PTT. However, accurate simulations can only be performed if the amount of AuNPs accumulated in the tumor is known. This study introduces Photo-Magnetic Imaging (PMI), which can appropriately recover the AuNP concentration to guide the PTT. Using multi-wavelength measurements, PMI can provide AuNP concentration based on their distinct absorption spectra. Tissue-simulating phantom studies are conducted to demonstrate the potential of PMI in recovering AuNP concentration for PTT planning. The recovered AuNP concentration is used to model the temperature increase accurately in a small inclusion representing tumor using a multiphysics solver that takes into account the light propagation and heat diffusion in turbid media.

Development of a preclinical CCD-based temperature modulated fluorescence tomography platform.

In preclinical research, fluorescence molecular tomography (FMT) is the most sensitive imaging modality to interrogate whole-body and provide 3D distribution of fluorescent contract agents. Despite its superior sensitivity, its mediocre spatial-resolution has been the main barrier to its clinical translation. This limitation is mainly due to the high scattering of optical photons in biological tissue together with the limited boundary measurements that lead to an undetermined and ill-posed inverse problem. To overcome the limitations of FMT, we previously introduced a novel method termed, Temperature Modulated Fluorescence Tomography (TMFT). TMFT utilizes thermos-sensitive fluorescent agents (ThermoDots) as a key component and localizes them with high-intensity focused ultrasound (HIFU). Scanning the focused HIFU beam having a diameter Ø = 1.3 mm across the tissue while monitoring the variation in the measured fluorescence signals reveals the position of the ThermoDots with high spatial accuracy. We have formerly built a prototype TMFT system that uses optical fibers for detection. In this paper, we present an upgraded version using a CCD camera-based detection that enables non-contact imaging. In this version, the animal under investigation is placed on an ultrasound transparent membrane, which eliminates the need for its immersion in optical matching fluids that were required by the fiber-based system. This CCD-based system will pave the way for convenient and wide-spread use of TMFT in preclinical research. Its performance validation on phantom studies demonstrates that high spatial-resolution (∼1.3 mm) and quantitative accuracy in recovered fluorophore concentration (<3% error) can be achieved.

Multiwavelength photo-magnetic imaging algorithm improved for direct chromophore concentration recovery using spectral constraints.

Multiwavelength photo-magnetic imaging (PMI) is a novel combination of diffuse optics and magnetic resonance imaging, to the best of our knowledge, that yields tissue chromophore concentration maps with high resolution and quantitative accuracy. Here, we present the first experimental results, to the best of our knowledge, obtained using a spectrally constrained PMI image reconstruction method, where chromophore concentration maps are directly recovered, unlike the conventional two-step approach that requires an intermediate step of reconstructing wavelength-dependent absorption coefficient maps. The imposition of the prior spectral information into the PMI inverse problem improves the reconstructed image quality and allows recovery of highly quantitative concentration maps, which are crucial for effective cancer detection and characterization. The obtained results demonstrate the higher performance of the direct reconstruction method. Indeed, the reconstructed concentration maps are not only of higher quality but also obtained approximately 2 times faster than the conventional method.

Multi-Wavelength Photo-Magnetic Imaging System for Photothermal Therapy Guidance.

BACKGROUND AND OBJECTIVES: In photothermal therapy, cancerous tissue is treated by the heat generated from absorbed light energy. For effective photothermal therapy, the parameters affecting the induced temperature should be determined before the treatment by modeling the increase in temperature via numerical simulations. However, accurate simulations can only be achieved when utilizing the accurate optical, thermal, and physiological properties of the treated tissue. Here, we propose a multi-wavelength photo-magnetic imaging (PMI) technique that provides quantitative and spatially resolved tissue optical absorption maps at any wavelength within the near-infrared (NIR) window to assist accurate photothermal therapy planning. STUDY DESIGN/MATERIALS AND METHODS: The study was conducted using our recently developed multi-wavelength PMI system, which operates at four laser wavelengths (760, 808, 860, and 980 nm). An agar tissue-simulating phantom containing water, lipid, and ink was illuminated using these wavelengths, and the slight internal laser-induced temperature rise was measured using magnetic resonance thermometry (MRT). The phantom optical absorption was recovered at the used wavelengths using our dedicated PMI image reconstruction algorithm. These absorption maps were then used to resolve the concentration of the tissue chromophores, and thus deduce its optical absorption spectrum in the NIR region based on the Beer-Lambert law. RESULTS: The optical absorption of the phantom was successfully recovered at the used four wavelengths with an average error of ~1.9%. The recovered absorption coefficient was then used to simulate temperature variations inside the phantom. A comparison between the modeled temperature maps and the MRT measured ones showed that these maps are in a good agreement with an average pseudo R2 statistic of 0.992. These absorption values were used to successfully recover the concentration of the used chromophores. Finally, these concentrations are used to accurately calculate the total absorption spectrum of the phantom in the NIR spectral window with an average error as low as ~2.3%. CONCLUSIONS: Multi-wavelength PMI demonstrated a great ability to assess the distribution of tissue chromophores, thus providing its total absorption at any wavelength within the NIR spectral range. Therefore, applications of photothermal therapy applied at NIR wavelengths can benefit from the absorption spectrum recovered by PMI to determine important parameters such as laser power as well as the laser exposure time needed to attain a specific increase in temperature prior to treatment. Lasers Surg. Med. 00:00-00, 2020. © 2020 Wiley Periodicals LLC.

Resolving tissue chromophore concentration at MRI resolution using multi-wavelength photo-magnetic imaging.

Photo-magnetic imaging (PMI) is an emerging optical imaging modality that showed great performance on providing absorption maps with high resolution and quantitative accuracy. As a multi-modality technology, PMI warms up the imaged object using a near infrared laser while temperature variation is measured using magnetic resonance imaging. By probing tissue at multiple wavelengths, concentration of the main tissue chromophores such as oxy- and deoxy-hemoglobin, lipid, and water are obtained then used to derive functional parameters such as total hemoglobin concentration and relative oxygen saturation. In this paper, we present a multi-wavelength PMI system that was custom-built to host five different laser wavelengths. After recovering the high-resolution absorption maps, a least-squared minimization process was used to resolve the different chromophore concentration. The performance of the system was experimentally tested on a phantom with two different dyes. Their concentrations were successfully assessed with high spatial resolution and average accuracy of nearly 80%.

A thermo-sensitive fluorescent agent based method for excitation light leakage rejection for fluorescence molecular tomography.

Fluorescence molecular tomography (FMT) is widely used in preclinical oncology research. FMT is the only imaging technique able to provide 3D distribution of fluorescent probes within thick highly scattering media. However, its integration into clinical medicine has been hampered by its low spatial resolution caused by the undetermined and ill-posed nature of its reconstruction algorithm. Another major factor degrading the quality of FMT images is the large backscattered excitation light component leaking through the rejection filters and coinciding with the weak fluorescent signal arising from a low tissue fluorescence concentration. In this paper, we present a new method based on the use of a novel thermo-sensitive fluorescence probe. In fact, the excitation light leakage is accurately estimated from a set of measurements performed at different temperatures and then is corrected for in the tomographic data. The obtained results show a considerable improvement in both spatial resolution and quantitative accuracy of FMT images due to the proper correction of fluorescent signals.

Extended photoacoustic transport model for characterization of red blood cell morphology in microchannel flow.

The dynamic response behavior of red blood cells holds the key to understanding red blood cell related diseases. In this regard, an understanding of the physiological functions of erythrocytes is significant before focusing on red blood cell aggregation in the microcirculatory system. In this work, we present a theoretical model for a photoacoustic signal that occurs when deformed red blood cells pass through a microfluidic channel. Using a Green's function approach, the photoacoustic pressure wave is obtained analytically by solving a combined Navier-Stokes and photoacoustic equation system. The photoacoustic wave expression includes determinant parameters for the cell deformability such as plasma viscosity, density, and red blood cell aggregation, as well as involving laser parameters such as beamwidth, pulse duration, and repetition rate. The effects of aggregation on blood rheology are also investigated. The results presented by this study show good agreements with the experimental ones in the literature. The comprehensive analytical solution of the extended photoacoustic transport model including a modified Morse type potential function sheds light on the dynamics of aggregate formation and demonstrates that the profile of a photoacoustic pressure wave has the potential for detecting and characterizing red blood cell aggregation.

Analysis of microcantilevers excited by pulsed-laser-induced photoacoustic waves.

This study presents a simulation-based analysis on the excitation of microcantilever in air using pulsed-laser-induced photoacoustic waves. A model was designed and coded to investigate the effects of consecutive photoacoustic waves, arising from a spherical light absorber illuminated by short laser pulses. The consecutiveness of the waves were adjusted with respect to the pulse repetition frequency of the laser to examine their cumulative effects on the oscillation of microcantilever. Using this approach, oscillation characteristics of two rectangular cantilevers with different resonant frequencies (16.9 kHz and 505.7 kHz) were investigated in the presence of the random oscillations. The results show that the effective responses of the microcantilevers to the consecutive photoacoustic waves provide steady-state oscillations, when the pulse repetition frequency matches to the fundamental resonant frequency or its lower harmonics. Another major finding is that being driven by the same photoacoustic pressure value, the high frequency cantilever tend to oscillate at higher amplitudes. Some of the issues emerging from these findings may find application area in atomic force microscopy actuation and photoacoustic signal detection.

Ex vivo validation of photo-magnetic imaging.

We recently introduced a new high-resolution diffuse optical imaging technique termed photo-magnetic imaging (PMI), which utilizes magnetic resonance thermometry (MRT) to monitor the 3D temperature distribution induced in a medium illuminated with a near-infrared light. The spatiotemporal temperature distribution due to light absorption can be accurately estimated using a combined photon propagation and heat diffusion model. High-resolution optical absorption images are then obtained by iteratively minimizing the error between the measured and modeled temperature distributions. We have previously demonstrated the feasibility of PMI with experimental studies using tissue simulating agarose phantoms. In this Letter, we present the preliminary ex vivo PMI results obtained with a chicken breast sample. Similarly to the results obtained on phantoms, the reconstructed images reveal that PMI can quantitatively resolve an inclusion with a 3 mm diameter embedded deep in a biological tissue sample with only 10% error. These encouraging results demonstrate the high performance of PMI in ex vivo biological tissue and its potential for in vivo imaging.

An analysis of beam parameters on proton-acoustic waves through an analytic approach.

It has been reported that acoustic waves are generated when a high-energy pulsed proton beam is deposited in a small volume within tissue. One possible application of proton-induced acoustics is to get real-time feedback for intra-treatment adjustments by monitoring such acoustic waves. A high spatial resolution in ultrasound imaging may reduce proton range uncertainty. Thus, it is crucial to understand the dependence of the acoustic waves on the proton beam characteristics. In this manuscript, firstly, an analytic solution for the proton-induced acoustic wave is presented to reveal the dependence of the signal on the beam parameters; then it is combined with an analytic approximation of the Bragg curve. The influence of the beam energy, pulse duration and beam diameter variation on the acoustic waveform are investigated. Further analysis is performed regarding the Fourier decomposition of the proton-acoustic signals. Our results show that the smaller spill time of the proton beam upsurges the amplitude of the acoustic wave for a constant number of protons, which is hence beneficial for dose monitoring. The increase in the energy of each individual proton in the beam leads to the spatial broadening of the Bragg curve, which also yields acoustic waves of greater amplitude. The pulse duration and the beam width of the proton beam do not affect the central frequency of the acoustic wave, but they change the amplitude of the spectral components.

Real-time photo-magnetic imaging.

We previously introduced a new high resolution diffuse optical imaging modality termed, photo-magnetic imaging (PMI). PMI irradiates the object under investigation with near-infrared light and monitors the variations of temperature using magnetic resonance thermometry (MRT). In this paper, we present a real-time PMI image reconstruction algorithm that uses analytic methods to solve the forward problem and assemble the Jacobian matrix much faster. The new algorithm is validated using real MRT measured temperature maps. In fact, it accelerates the reconstruction process by more than 250 times compared to a single iteration of the FEM-based algorithm, which opens the possibility for the real-time PMI.

Comprehensive analytical model for CW laser induced heat in turbid media.

In this work, we present a new analytical approach to model continuous wave laser induced temperature in highly homogeneous turbid media. First, the diffusion equation is used to model light transport and a comprehensive solution is derived analytically by obtaining a special Greens' function. Next, the time-dependent bio-heat equation is used to describe the induced heat increase and propagation within the medium. The bio-heat equation is solved analytically utilizing the separation of variables technique. Our theoretical model is successfully validated using numerical simulations and experimental studies with agarose phantoms and ex-vivo chicken breast samples. The encouraging results show that our method can be implemented as a simulation tool to determine important laser parameters that govern the magnitude of temperature rise within homogenous biological tissue or organs.

Analytical reconstruction of the bioluminescent source with priors.

Bioluminescence imaging has been a popular tool in small animal imaging. During the last decade, the efforts have focused on the development of tomographic systems. However, due to the difficulties in the nature of inverse source problem, multi-modal systems have been the center of attention for the last couple of years. These systems provide complementary information such that the difficulties of the inverse source problem could be overcome using the a priori information obtained. Motivated by these advances in multi-modal systems, this work presents a novel analytical reconstruction of the bioluminescent source. It is shown that if source strength is known a priori then source position could be calculated or vice versa, if source location is known a priori, source strength could be calculated as well as the photon fluence rate. The determination of the source location can be achieved by another imaging system such as X-ray computed tomography. Therefore, in bioluminescence tomography together with an imaging system can be utilized as a multi-modal system. In this work, conventional finite element based simulations are also performed and the numerical results are compared with the analytical ones. It turns out to be that the analytical results are in a good accordance with the numerical results.

Photoacoustic radiation force on a microbubble.

We investigate the radiation force on a microbubble due to the photoacoustic wave which is generated by using a pulsed laser. In particular, we focus on the dependence of pulsed laser parameters on the radiation force. In order to do so, we first obtain a new and comprehensive analytical solution to the photoacoustic wave equation based on the Fourier transform for various absorption profiles. Then, we write an expression of the radiation force containing explicit laser parameters, pulse duration, and beamwidth of the laser. Furthermore, we calculate the primary radiation force acting on a microbubble. We show that laser parameters and the position of the microbubble relative to a photoacoustic source have a considerable effect on the primary radiation force. By means of recent developments in laser technologies that render tunability of pulse duration and repetition frequency possible, an adjustable radiation force can be applied to microbubbles. High spatial control of applied force is ensured on account of smaller focal spots achievable by focused optics. In this context, conventional piezoelectric acoustic source applications could be surpassed. In addition, it is possible to increase the radiation force by making source wavelength with the absorption peak of absorber concurrent. The application of photoacoustic radiation force can open a cache of opportunities such as manipulation of microbubbles used as contrast agents and as carrier vehicles for drugs and genes with a desired force along with in vivo applications.

Virtual source method for diffuse optical imaging.

The Green's function for diffusive wave propagation can be obtained by utilizing the representation theorems of the convolution type and the correlation type. In this work, the Green's function is retrieved by making use of the Robin boundary condition and the representation theorems for diffusive media. The diffusive Green's function between two detectors for photon flux is calculated by combining detector readings due to point light sources and utilizing virtual light sources at the detector positions in optical tomography. Two dimensional simulations for a circular region with eight sources and eight detectors located on the boundary are performed using a finite element method to demonstrate the feasibility of virtual sources. The most important potential application would be the replacement of noisy measurements with synthetic measurements that are provided by the virtual sources. This becomes an important issue in small animal and human studies. In addition, the same method may also be used to reduce the imaging time.