Journal of Biomedical Optics最新文献

Significance: Optical coherence elastography (OCE) is a noninvasive imaging technique with high sensitivity and resolution that can be used for mucocutaneous imaging. Oral submucous fibrosis (OSF) is a chronic disease that has a tendency to become cancerous. Nevertheless, there are a few noninvasive methods for early detection of OSF.

Aim: A piezoelectric transducer-based (PZT) OCE technique was devised to noninvasively assess the structural and mechanical properties of mucosa in healthy and fibrotic oral diseases.

Approach: We first validated the accuracy and reliability of the OCE system for tissue elasticity detection by means of a heterogeneous agar model. The structural and biomechanical characteristics of the regional tissues were then evaluated by examining the oral mucosa of both healthy and fibrotic SD rats.

Results: Normal and fibrotic tissue stiffness differed significantly ( $p<0.05$ ). The elastic wave velocity was $6.44\pm 0.30m/s$ in the normal group and $14.2\pm 0.91m/s$ in the fibrotic group. After converting the results to Young's modulus, the stiffness of the healthy buccal tissues and the fibrotic buccal tissues were $130.71\pm 12.01$ and $636.15\pm 79.17\mathrm{kPa}$ , respectively ( $p<0.05$ ).

Conclusions: OCE can differentiate between normal and fibrotic tissue based on elasticity and optical properties. Healthy buccal tissues were softer than diseased tissues.

Significance: Frequency-domain near-infrared spectroscopy (FD-NIRS) currently enables absolute hemoglobin quantification but requires multidistance measurements of both amplitude attenuation and phase shifts. Notably, existing FD-NIRS approaches have not demonstrated reliable quantification of differential redox-state concentrations of cytochrome c oxidase ( ${\mathrm{CCO}}_{\text{redox}}$ ), a critical metabolic marker.

Aim: We aimed to develop a novel optimization-based algorithm for single source-detector (S-D), phase-only FD-NIRS that achieves accurate quantifications of hemoglobin parameters (HbO and Hb) and ${\mathrm{CCO}}_{\text{redox}}$ .

Approach: Our computational framework implemented both forward modeling and inverse reconstruction. For the modeling, we first defined chromophore concentration sets (HbO, Hb, ${\mathrm{CCO}}_{\text{redox}}$ ), followed by calculations of wavelength-dependent optical properties for two- or eight-wavelength configurations. Next, time-domain photon propagation was generated via Monte Carlo (MC) simulations, and FD-NIRS parameters (modulation amplitude, phase) were extracted through Fourier analysis. In the inverse computation, nonlinear optimization with edge-barrier regularization was employed for the recovery of chromophore concentrations. Both the multiseparation method and the single S-D, phase-only algorithm were used to reconstruct chromophore concentrations.

Results: Respective performances evaluated for the two methods were compared through their concentration recovery accuracy. In either the two- or eight-wavelength configuration, our new algorithm outperformed the conventional method for the S-D separations up to 3 cm for all three chromophores. In particular, ${\mathrm{CCO}}_{\text{redox}}$ estimation was improved markedly from a mean relative error of 34.1% with the conventional method to just 5.1% using our algorithm.

Conclusions: These results validate single-separation phase-only FD-NIRS as an accurate method for multichromophore quantification (including ${\mathrm{CCO}}_{\text{redox}}$ ), enabling simpler, cost-effective systems without compromising metabolic imaging capability. The approach achieves $<10\%$ error in hemoglobin quantification while eliminating traditional multidistance requirements.

Significance: Photoacoustic tomography (PAT) is an emerging biomedical imaging technology that offers high contrast and high resolution, showing great potential for applications in medical imaging. However, existing regularization methods often lead to instability and artifacts in the reconstruction due to imbalanced regularization parameter settings. To address these issues, we propose a reconstruction algorithm based on the L-alternating direction method of multipliers (ADMM) for PAT, which significantly improves image reconstruction quality and has high clinical application potential.

Aim: We introduce a nonconvex L1-L2 norm into the variational model and employ the ADMM to decompose the optimization problem into efficiently solvable subproblems. A preconditioned conjugate gradient (PCG) method is further integrated to accelerate the solution of linear systems, thereby improving both reconstruction accuracy and computational efficiency.

Approach: We propose an L-ADMM framework with adaptive weighted L1-L2 regularization for PAT reconstruction. The method employs ADMM to split the optimization into tractable subproblems and uses PCG to efficiently solve linear systems. It achieves stable, high-quality reconstruction under sparse sampling by enhancing sparsity while preserving structural details.

Results: Experiments on vascular and breast models demonstrate that, even with only 64 transducers under sparse sampling, the proposed L-ADMM method achieves peak signal-to-noise ratio values of 37.24 and 36.26 dB and structural similarity index measure values of 0.9766 and 0.9665, respectively. Compared with L2, L1 + L2, L1-L2, TV regularization, and U-Net methods, the proposed algorithm substantially improves image quality, highlighting its feasibility for cost-effective clinical PAT.

Conclusions: The proposed L-ADMM-based reconstruction algorithm, by integrating adaptive regularization with efficient optimization, significantly improves PAT image quality under sparse sampling conditions, offering a feasible solution with strong potential for clinical translation.

Significance: Photodynamic therapy (PDT) agents activated by near-infrared (NIR) light have demonstrated effectiveness in animal studies. However, clinical trials in humans are lacking due to biocompatibility concerns. We evaluate the feasibility of NIR-PDT using newly developed upconversion nanoparticles-quantum dots-Rose Bengal (UCQRs) through Monte Carlo simulations.

Aim: Surgery, the primary treatment mode for breast cancer, often reduces the quality of life due to scarring, necessitating a less invasive alternative. Herein, we propose an NIR-PDT approach using UCQRs to treat patients with early-stage breast cancer. The treatment can be performed on patients in the prone position using light irradiation alone, significantly reducing the burden on patients. In NIR-PDT using UCQR, a treatment depth of 3 to 4 cm can be expected based on the penetration depth of the 808-nm excitation light.

Approach: We created 150 digital breast phantoms by reconstructing breast slice images from breast computed tomography scans. These phantoms were classified by breast density and tumor depth, and simulations were performed on representative models. The therapeutic effect of NIR-PDT was assessed based on the amount of singlet oxygen generated, calculated from the fluence in the tumor voxels.

Results: The simulations indicated that tumor depth had a greater impact on the therapeutic outcomes compared with breast contour or structure. In all phantoms where tumors with a 7-mm diameter were embedded at depths of 15 to 25 mm, the generated singlet oxygen exceeded the cell death threshold across all tumor voxels. Shallow tumors between 15 and 20 mm can be treated with 15 or fewer irradiations, whereas deep tumors between 20 and 25 mm are estimated to require up to 45 irradiations.

Conclusions: This virtual clinical trial using 150 digital phantoms suggests that NIR-PDT with UCQRs offers a promising, minimally invasive alternative for treating breast cancer.

Significance: Cancer is one of the leading diseases worldwide, continuing to pose a significant financial burden to national health systems and taking lives. These drive the development of early-stage cancer diagnostics, which is believed to be a crucial step in improving patients' life expectancy and long-term outcomes of cancer treatments.

Aim: In this review, we explore the potential of a label-free technique known as Brillouin microscopy, a type of optical elastography, emerging as a promising candidate for early-stage cancer screening.

Approach: We discuss the main principles of this advanced imaging technology and provide a thorough analysis of all known Brillouin microscopy reports in application to cancer research and diagnostics. In our analysis, we focus on the mechanobiological aspect of the disease and draw conclusions based on four main sample types: cell cultures, cells in microfluidic environments, organoids, and excised tissues.

Results: We review recent advancements in cancer detection, finding that the technique can consistently biomechanically delineate between healthy and unhealthy cells, and organoids and tissues across multiple cancer types. We also present strides made in imaging mechanical changes in cancer during varying stages of progression, treatment, and regression.

Conclusions: We conclude this review with our perspective on the key developments required for technology's translation into the clinical realm, including measurement standardization, inclusion of statistical and artificial intelligence methods into data analysis and automated diagnosis, and further hardware developments needed for in situ and in vivo micromechanical measurements.

Significance: Noninvasive imaging to accurately measure subtle changes in tumor size is underutilized when assessing therapeutic responses in the skin. During photodynamic therapy (PDT) for basal cell carcinoma (BCC), a better definition of the tumor size threshold for PDT responsiveness is needed.

Aim: We aim to quantitatively demonstrate the first clinical evidence of tumor shrinkage after multiple rounds of PDT using a robust measurement and analysis approach.

Approach: Tumors were monitored experimentally using a 3D camera and software system (stereo photogrammetry). A total of 122 BCC tumors in 35 patients were treated with PDT (5-ALA and blue light) in three sessions. Calculated volumes and heights were used to plot changes in tumor size.

Results: In total, 70% of BCC cleared completely. Measured heights correlated with histological tumor depth; average heights were $\sim 10\%$ to 20% of actual tumor depth. From photogrammetry at baseline, an average height of $<0.15\mathrm{mm}$ was found to predict a complete therapeutic response. Thus, our 3D morphometric technique provides a surrogate measure of BCC tumor depth that predicts PDT response and is accurate to well below the millimeter level.

Conclusions: 3D photogrammetry can inform the selection of BCC tumors for PDT with exceptionally high spatial accuracy, dramatically better than can be quantified by a clinician.

Significance: The bone marrow is essential in immune regulation to maintain body homeostasis and to control the trafficking of stromal cells. A framework of connective tissue upholds bone marrow cells to maintain their mechanical and functional integrity. The biomechanical characterization of the bone marrow may provide useful insights for diagnosing hematologic diseases such as primary myelofibrosis. Optical coherence elastography (OCE) can measure the mechanical properties of tissues with high spatiotemporal resolution and may be well-suited for characterizing bone marrow elasticity.

Aim: We demonstrate the quantification of the elastic modulus of bone marrow ex vivo at different locations along the diaphysis of mice femurs and compare the elastic modulus within different age groups of mice femurs.

Approach: The femur bone marrow of CD1 mice, $\sim 12$ weeks old (young adult), 24 weeks old (mature adult), and 1 year old (old adult), was imaged with OCE ( $N=4$ femurs for each age group) to investigate the change in stiffness with age and location along the femur. A noncontact air-coupled ultrasound (ACUS) transducer induced elastic waves in the bone marrow, which were detected by phase-sensitive optical coherence tomography. The ACUS-OCE measurements were taken at three different locations along the diaphysis from the proximal end to the distal end to investigate the spatial stiffness variations.

Results: The results show that the stiffness of femoral bone marrow increases significantly with age ( $p<0.001$ ), but there was no significant difference in Young's moduli among the locations for young ( ${\chi }^2\left(2\right)=2.15$ , $p=0.33$ ), mature ( ${\chi }^2\left(2\right)=5.68$ , $p=0.058$ ), and old ( ${\chi }^2\left(2\right)=5.73$ , $p=0.056$ ) mice femur samples.

Conclusions: These findings show that OCE is promising for mapping the stiffness of the intact bone marrow and could be used for minimally invasive clinical applications.

Significance: Intralipid, a soybean oil-based lipid emulsion, is widely used in photomedicine to enhance light distribution due to its strong scattering properties. Although the optical characteristics of Intralipid are well documented, interactions with the reactive molecular species (RMS) generated during photodynamic therapy (PDT) and the impact of such interactions on therapeutic outcomes remain poorly understood. We reveal that Intralipid actively influences PDT response in vitro, beyond its role as a scattering agent.

Aim: We examined how Intralipid affects the optical and photodynamic behavior of benzoporphyrin derivative (BPD), a clinical photosensitizer, in solution and across four ovarian cancer cell lines.

Approach: The photodynamic properties of BPD, with and without Intralipid, were analyzed using fluorescence spectrometry and RMS probes, and PDT-induced oxidation of Intralipid components was characterized using LC-MS. The effects of Intralipid on BPD-PDT were evaluated under various conditions.

Results: Intralipid reduced BPD photobleaching and RMS generation, suggesting RMS quenching. Extensive oxidation of Intralipid components was observed following PDT. Finally, Intralipid significantly modified BPD-PDT efficacy across all four cell lines, depending on photosensitizer-light interval, dose, and incubation time.

Conclusions: Intralipid acts as a bioactive modulator of PDT response, highlighting the need for further investigations both in vitro and in vivo.

Significance: Dynamic optical coherence elastography can excite and detect propagating mechanical waves in soft tissue without physical contact and in near real time. However, most soft tissue is anisotropic, characterized by at least three independent elastic moduli. As a result, reconstructing these moduli from mechanical wave fields requires a complex procedure.

Aim: We consider a nearly incompressible transverse isotropic (NITI) material, which has been shown to locally define the symmetry of many soft tissues such as muscle, tendon, skin, cornea, heart, and brain. Reconstruction of elastic moduli in the NITI medium using Rayleigh waves is addressed here. A method to accurately compute the angular dependence of Rayleigh wave phase velocity for the most common geometries (point-like and line sources) of mechanical wave excitation is described.

Approach: When a line source is used to launch plane mechanical waves over the medium surface, the phase velocity of Rayleigh waves in the direction of propagation is directly accessible. For a point-like source, propagation of the energy flux is tracked (i.e., its group velocity), which cannot be directly used for moduli inversion. In this case, angular spectrum decomposition is used to access the phase velocity. Both numerical simulations in OnScale and experiments in a stretched PVA phantom were performed.

Results: We show that both methods (line source wave excitation and angular decomposition from a point-like source) produce similar results and accurately estimate the angular anisotropy of the Rayleigh wave phase velocity. We also explicitly show that a commonly used group velocity approach leads to inadequate moduli inversion and should not be used for reconstruction.

Conclusions: We suggest that the line source is best when a surface area must be scanned, whereas the point-like source with the proposed phase velocity reconstruction is best for single-point moduli estimation or when tissue motion is a concern.

Significance: 5-Aminolevulinic acid (5-ALA) is a medical pro-drug used to induce the intracellular production of protoporphyrin IX (PpIX) via the heme synthesis pathway. Discoveries in mechanisms and developments in novel applications still continue with this uniquely endogenous intracellular optical system.

Aim: Understanding and exploiting the growing uses can be advanced through a survey of knowledge on the mechanisms and biokinetics of 5-ALA administration, partitioning, PpIX production, localization changes, clearance mechanisms, biological interactions, and methods for unique activation methods in both diagnostic and therapeutic applications.

Approach: The current medical uses of PpIX are reviewed, separating into therapeutic and diagnostic areas, and the expansion and lateral growth areas are outlined.

Results: Initially approved for photodynamic therapy of skin lesions, fluorescence diagnostic indications later developed to guide surgical resection in bladder cancer and glioma. Today, the 5-ALA-PpIX system's spatial-temporal complexity in photophysics and pharmacokinetics continues to lead to more uses, such as photodynamic priming to alter tissue, fast intracellular tissue oxygen sensing, infection, and burn imaging and therapy.

Conclusions: The 5-ALA-PpIX system has broad potential partly because of the ubiquity of the heme synthesis across many cell/tissue types, combined with natural selectivity, unique pharmacokinetics, bright fluorescence, and sufficiently strong singlet oxygen production.