Niche preclinical and clinical applications of photoacoustic imaging with endogenous contrast

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TL;DR

This review summarizes niche preclinical and clinical applications of photoacoustic (PA) imaging using endogenous contrast agents such as hemoglobin, melanin, collagen, water, and glucose. It highlights PA imaging's ability to provide functional information (e.g., oxygen saturation) and guide surgical and interventional procedures without exogenous contrast. The clinical significance lies in its potential for non-invasive, real-time diagnostics and therapy monitoring, particularly in oncology, vascular diseases, and image-guided interventions.

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**Background:** Photoacoustic (PA) imaging is a non-ionizing modality that generates ultrasound waves from nanosecond-pulsed light absorption and thermoelastic expansion of chromophores. Endogenous chromophores like hemoglobin, melanin, collagen, water, and glucose provide contrast without exogenous agents. This review focuses on niche preclinical and clinical applications of PA imaging using endogenous contrast, covering diagnostic and image-guided therapy applications. The authors note that a PubMed query yielded 5086 articles on photoacoustic/optoacoustic imaging, with 438 review articles; among these, 115 (∼26%) were on applications or technological advancements, and 8.5% on contrast agents. The number of publications has risen exponentially.

**Methods:** This is a narrative review summarizing selected preclinical and clinical studies. The authors searched PubMed with keywords "Photoacoustic" OR "Optoacoustic" and applied exclusion criteria (non-biological applications, case studies, non-English articles, magazine articles). They identified 438 review articles and further categorized them. The review is divided into diagnostic applications (vasculature and blood oxygen saturation, melanin, collagen and water, glucose) and image-guided therapy applications (surgical guidance, thermometry, lesion assessment, therapy monitoring).

**Key Results:** - **Vasculature and oxygen saturation:** PA imaging can map blood vessels and oxygen saturation (sO2) using spectroscopic unmixing of oxy- and deoxyhemoglobin. Examples include imaging of palm vessels (Fig. 1ii), somatosensory cortex response (Fig. 1iii), and breast vasculature (Fig. 1iv). Several preclinical studies (Table 1) used PA imaging to monitor tumor vascular function and oxygenation in response to therapies (e.g., photodynamic therapy, bevacizumab, radiation). For breast cancer, systems like Twente PA Mammoscope (TPAM), LOUISA-3D, SBH-PACT, and the FDA-approved Imagio system were described. Imagio provides relative total hemoglobin concentration and sO2 maps; it is the only FDA-approved PA system for breast cancer detection. - **Melanin:** Melanin has a broad absorption spectrum (400–1064 nm). Applications include ocular imaging (retinal pigment epithelium, choroid), detection of circulating metastatic melanoma cells, and skin melanoma assessment. Table 2 lists studies with imaging depths up to 4 cm (e.g., human skin in vivo at 850 nm). PA imaging can measure melanoma thickness and guide biopsy. - **Collagen and water:** Collagen content was quantified in Duchenne muscular dystrophy (DMD) patients using multispectral optoacoustic tomography (MSOT); collagen mean/max signals significantly differed between healthy and DMD subjects (Fig. 4iii). In atherosclerosis, intravascular PA imaging (IVPA) at 680–900 nm differentiated collagen types I and III in plaques (Fig. 4i-ii). For cervical remodeling, water-to-collagen ratio was measured ex vivo in murine cervices at gestational ages 13.5 and 19.5 dpc (Fig. 5ii). - **Glucose:** Glucose was quantified in aqueous solutions using mid-infrared photoacoustic spectroscopy (coefficient of determination = 0.8) (Fig. 6i). In vivo, raster scanning at 90 µm resolution required ∼4.3 minutes per measurement (Fig. 6ii). - **Image-guided procedures:** PA imaging tracked biopsy needles (Table 3, Fig. 7a-b), guided robotic surgeries (da Vinci system, Fig. 7c-f), spinal surgeries (differentiating nerve and tendon, Fig. 7g-h), stent placement (3D reconstruction, Fig. 7i-k), breast lumpectomy (UV-PAM vs. H&E, Fig. 7l-m), EVLA catheter tip tracking (Fig. 7n), and brachytherapy seed placement (Fig. 7o-p). - **Thermometry and lesion assessment:** PA imaging monitored temperature during cryotherapy (Fig. 8a-b), MIFU therapy (Fig. 8c-d), EVLA (Fig. 8e), and PTT (Fig. 8f). In cardiac ablation, spectroscopic PA imaging at 740–780 nm differentiated ablated and non-ablated myocardium (Fig. 8g-j). In liver ablation, PA signal decreased in ablated tissue. - **Non-oncologic applications:** PA imaging detected strokes in mice (blood flow drop to 34.13% of nominal at 60 min post-ischemia), monitored placental oxygenation (Fig. 9a), and assessed rheumatoid arthritis (hypoxia and neovascularization).

**Clinical Implications:** PA imaging with endogenous contrast offers non-invasive, real-time functional and structural information without ionizing radiation or exogenous agents. It has potential for improving diagnosis and therapy monitoring in breast cancer, melanoma, cardiovascular disease, stroke, and inflammatory arthritis. The FDA approval of the Imagio system for breast cancer marks a key milestone. Challenges include limited penetration depth, low temporal resolution, need for fluence compensation, and laser safety (ANSI MPE: 20 mJ/cm² at 532 nm). Advances in LED-based systems, deep learning for artifact reduction and spectral unmixing, and NIR II window imaging may overcome these limitations.