Optoacoustic Imaging: Comparison
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Please note this is a comparison between Version 2 by Vicky Zhou and Version 1 by Emma Brown.

Optoacoustic or photoacoustic imaging (OAI/PAI) has the unique ability and scalability to visualize, monitor, and understand the molecular mechanisms of inflammation.

  • optoacoustics
  • photoacoustics
  • imaging inflammation
  • MSOT
  • RSOM
  • PAI
  • acute inflammation
  • chronic inflammation
  • molecular imaging

1. Introduction

Optoacoustic imaging (OAI) encompasses a set of heterogenous optical imaging technologies utilizing the photoacoustic effect. Based on the observation of Alexander Graham Bell that there is formation of sound waves following light absorption [1], the principle has been rediscovered and used to develop imaging approaches [2]. In OAI, optoacoustic contrast arises when the light is absorbed by tissue molecules and converted into acoustic pressure waves, which can be recorded and formed into optoacoustic images [3].

Due to their unique absorption characteristics, endogenous molecules such as deoxyhemoglobin, oxyhemoglobin, collagen, lipids, and melanin enable OAI in the near-infrared (NIR) range [3][4] (Figure 1). In the future, targeted exogenous probes or contrast agents may further enrich the clinical capability of this technology by specifically labeling target molecules or cells for more personalized imaging approaches [1][5][6][7][8]. OAI is able to detect a broad range of endogenous and exogenous molecules within a single imaging modality whilst maintaining high spatial resolution at greater depths compared to optical imaging, due to the detection of ultrasound (US) waves, which scatter less in tissue than light [2][9]. The non-invasive nature of OAI will allow broad application to both experimental and clinical settings without interfering with biological processes.

Figure 1. Absorption coefficients (µa in cm−1) versus wavelength (in nm) for different optoacoustic imaging molecules and tissue. Spectra were derived from existing data as indicated: melanin (https://omlc.org/spectra/melanin/mua.html as derived from [10][11][12][13]), oxy- (HbO2) and deoxyhemoglobin (HbR) (https://omlc.org/spectra/hemoglobin/summary.html), (bulk) lipid (https://omlc.org/spectra/fat/fat.txt as derived from [14]), water (https://omlc.org/spectra/water/data/hale73.txt derived from [15]), aorta tissue (https://omlc.org/spectra/aorta/oraevsky_a.txt derived from [16]), and collagen (extracted from [17]). All databases accessed on 9 April 2021.

2. Optoacoustic Imaging of Inflammation: Applications

Table 2Table 1 gives an overview of selected studies.

Table 21. Selected inflammatory diseases studied with OAI. ICG = indocyanine green, NET = near-infrared erythrocyte-derived transducers, NP = nanoparticle, VEGF = Vascular endothelial growth factor, TNF α = tumor necrosis factor-α.

Diseases Condition Stage Target/Contrast Reference
Cardiovascular Atherosclerosis Preclinical Lipid [18][19][20][21][22][23][24][25][26]
Atherosclerosis Preclinical CD36 targeted NP [27]
Atherosclerosis Preclinical ICG loaded NETs [28]
Atherosclerosis Preclinical Gold nanoparticles [29]
Foot vasculature Clinical Hemoglobin [30]
Vascular malformations Clinical Hemoglobin [31]
Carotid arteries Clinical Hemoglobin [32]
Peripheral artery disease Clinical Hemoglobin [33]
Dermatologic Thermal injuries Preclinical Hemoglobin [34][35][36]
LPS-induced wound inflammation Preclinical Hemoglobin [37]
Bacterial wound infection Preclinical Targeted sugars [38][39]
Skin microvasculature, layers Clinical Hemoglobin [40][41]
Psoriasis Clinical Hemoglobin [42][43]
Atopic dermatitis Clinical Hemoglobin [44][45]
Gastrointestinal Acute liver damage Preclinical ICG Perfusion [46]
Acute liver damage Preclinical Probes, NO, H2S and leucine aminopeptidase [47][48][49]
Liver fibrosis Preclinical Collagen [50]
Intestinal strictures Preclinical Collagen [51][52]
Intestinal inflammation Preclinical Hemoglobin [53][54]
Image-guided surgery Preclinical Hemoglobin [53]
Intestinal vasculature and lymphatic vessels Preclinical Hemoglobin, Evans blue dye [54]
Intestinal inflammation Clinical Hemoglobin [55][56]
Musculoskeletal Arthritis Preclinical NP: targeting L-selectin/P-selectin, TNFα, VEGF [57][58][59]
Rheumatoid arthritis Clinical Hemoglobin [60]
Enthesitis Clinical Hemoglobin [61]
Systemic sclerosis Clinical Hemoglobin [31][62]
Neurodegenerative Alzheimer’s diseases Preclinical CDnir7 [63]
Cerebrovascular damage Preclinical Hemoglobin [64]
  Muscular dystrophy Clinical Collagen [65]
Kidney Organ perfusion Preclinical ICG Perfusion [66]
Acute injury Preclinical NP [67]
Organ transplant Clinical Collagen [68]
Gynecologic Preeclampsia Preclinical Hemoglobin [69][70]
Preeclampsia Preclinical ICG targeting FRα [71]

Limitations of OAI

Despite its remarkable potential to image inflammation in a clinical setting, OAI has several limitations. Until now, penetration depths have still been limited to a few centimeters (up to ~7 cm), which limits the imaging of organs at depth, especially in patients with a high body mass index (BMI). However, not only increased body fat, but also the natural heterogenous fat distribution in different genders is a limiting factor [72]. OA endoscopy approaches may bypass this depth limitation in some scenarios. In addition, patients with increased hair or darker skin (skin type 4 to 6 on the Fitzpatrick scale) present a challenge due to the high level of light absorption by melanin, which will significantly reduce the light energy (fluence) reaching deeper tissue. Comparable problems are seen in animals with melanin expression (e.g., C57BL6 and others), limiting options for in vivo animal models with intact immune systems. The problem of wavelength- and depth-dependent decreases in light fluence distribution becomes more pronounced in deep tissues, causing errors in estimating blood oxygen saturation differences [73] in particular. Correcting for spectral distortions of illumination light as it passes through tissue would allow the absolute quantification of optoacoustic molecules, but it remains a significant challenge to apply in vivo and hence is an active area of research in the field [73][74].

A topic currently under investigation is the standardization of OAI measurements, especially in quantitative measurements for clinical applications [75][76]. Even though there is evidence for repeatable and stable OAI measurements over time [72], their use is still far from clinical “routine”. To aid clinical translation, the clinician would also require more intuitive approaches to interpret optoacoustic images, preferably together with sufficient familiar anatomical information. Therefore, a hybrid imaging approach together with co-registration of (high-resolution) B-mode US signals is highly important [77][78]. The use of exogenous contrast agents to specifically label target molecules should be conducted with caution, owing to the possible toxicities associated with their administration [79].

Finally, most of the clinical studies conducted to date have been observational and/or conducted on a limited number of patients. The studies have not impacted the clinical decision-making of the patient. Therefore, the true impact and benefits of using OAI in clinical inflammation imaging need to be assessed in multi-center prospective studies, of which there is one study currently underway in Europe (https://euphoria2020.eu, last access: 9 April 2021, ClinicalTrials.gov Identifier: NCT04456400).

3. Conclusions

OAI is an emerging non-invasive imaging modality which has already had significant impact on unravelling the pathophysiology of inflammation in preclinical and clinical scenarios. OAI provides a multi-scale perspective of inflammatory processes, monitoring both structural and functional aspects at various anatomical locations, resolutions, and imaging depths. Besides visualizing strong absorbing hemoglobin, and therefore vascular structure, future approaches will focus on novel endogenous, as well as exogenous, OA compounds.

OAI may be sensitive enough to detect even slight inflammatory changes in tissues, therefore enabling early or even preventive treatment strategies. Despite the first preclinical studies, OAI awaits the translation of novel contrast agents for imaging inflammatory cells or microorganisms [80]. This approach could also enable the targeted delivery of functionalized multimodal and theranostic compounds to abnormal tissues while sparing the other organ systems [81][82][83]. At the same time, a high signal intensity and a high degree of biodegradation is required when administered in humans [84].

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