Diagnostic imaging: Listening in to skin disease

Optoacoustic mesoscopy promises to be a fast and reliable non-invasive method for the diagnosis of psoriasis.

Histological analysis of a tissue biopsy is the current gold standard used by dermatologists1. Dermoscopy, on the other hand, is non-invasive, allowing for the in vivo evaluation of microstructures of the epidermis, the dermoepidermal junction and the papillary dermis. Although such skin structures are not visible to the naked eye, their detection is important because they correlate to diagnostic histological features. Dermoscopy facilitates the distinction between a malignant or a benign pigmented skin lesion, because the method defines structures by using a distribution of colours to identify patterns. However, dermoscopy can only be performed by expert clinicians2, and is therefore not widely accessible. Indeed, the clinician's experience is invaluable in the diagnosis of skin conditions and in the evaluation of the efficacy of treatment at follow-up, because methods that standardize diagnosis and that aid the clinician in making an informed decision have significant drawbacks.

Some skin pathologies can be diagnosed with other non-invasive high-resolution imaging technologies such as laser confocal microscopy or two-photon microscopy. However, these techniques can only image the superficial layers of the skin (for example, for confocal imaging, the epidermis and papillary dermis)3,4, yet key features of many inflammatory and non-inflammatory skin conditions occur in the deep and reticular dermis. In addition, neither confocal microscopy nor two-photon microscopy can provide a functional readout that reflects, for example, changes in vascular architecture across the dermal layers in a diseased state. In contrast, ultrasound-based methods, such as echography, reach deeper layers of the skin, and high-resolution variable-frequency ultrasound imaging is increasingly being used in the non-invasive evaluation of various cutaneous diseases. These ultrasound-based methods play a complementary role to physical examination in the assessment of superficial cutaneous lesions, are particularly useful in the assessment of lesions that are too small to be evaluated by computed tomography or magnetic resonance imaging, and reduce the need for invasive procedures such as biopsies and fine-needle aspirations. Specifically, the echographic evaluation of cutaneous lesions is typically carried out with linear-array high-frequency transducers (at a bandwidth of 6–18 MHz) operating at standardized scanner settings. Colour Doppler and power Doppler methods can then be used to assess the vascularity of the lesions5. Yet all these ultrasound-based techniques suffer from low resolution, which is particularly evident for thin epidermal structures. The use of ultrasound is currently therefore mainly limited to assessing changes in the size of skin lesions after treatment, and is rarely used for clinical diagnosis or for the evaluation of the severity of skin diseases. Writing in Nature Biomedical Engineering, Vasilis Ntziachristos and colleagues now demonstrate an optoacoustic mesoscopy method, implemented in a portable device, that can image the skin with the sensitivity of laser confocal microscopy and the penetration depth of echography6. The researchers tested the imaging device in a patient cohort suffering from psoriasis to visualize pathophysiological skin features previously undetected by other non-invasive techniques.

Ntziachristos and co-authors' method, named ultra-broadband raster-scanning optoacoustic mesoscopy (UB-RSOM), involves ultrashort photon pulses (<2 ns) that result in signals across an ultra-broad, ultrasound frequency spectrum. To detect the optoacoustic signals at high numerical apertures (>60°), they used a focused transducer comprising a LiNbO3 crystal, which yields at least an order-of-magnitude higher spatial-frequency range (10–180 MHz) than ultrasound imaging. Optoacoustic detection works by detecting the acoustic signal that is generated as a result of light absorption by tissue. This allows a tomographic reconstruction of absorption contrast, quantifying features associated with dermal angiogenesis and skin inflammation, without the use of contrast agents, with unprecedented resolution-to-depth ratio. The first application of UB-RSOM was for the quantification of psoriasis inflammation.

Psoriasis is a chronic inflammatory disease of the skin that is histologically characterized by epidermal hyperplasia, inflammatory-cell infiltration in the dermis, and intense neovascularization7. The UB-RSOM method was able to visualize and measure the thickness of the epidermis, dermis and the horizontal vascular plexus of the dermis, as well as the mean diameter of blood capillary loops, with similar sensitivity to what can be achieved with histology (Fig. 1). All the main histological features of psoriatic skin were visualized at a resolution-to-depth ratio not possible with other imaging modalities. Moreover, from the main features of psoriatic skin, Ntziachristos and co-authors computed a new index of optoacoustic features of psoriasis that strongly correlated with the main clinical measure of the severity of this skin disease. When the portable probe was used to image other skin diseases (eczema, vasculitis and nevus), the authors observed features that had never been seen before.

Figure 1: Imaging the skin with photoacoustic mesoscopy.
figure1

a, Portable probe, consisting of a scanning head, which contains a transducer and fibre bundles for illumination, and an articulated arm that helps fix the probe to the area to be imaged. b, Haematoxylin and eosin histology images (left) and optoacoustic images (right) of psoriatic skin (top) and healthy skin (bottom). In the optoacoustic images, the colour of the biological structures depends on the frequency of their corresponding optoacoustic signals. The epidermis (EP) appears in green, and can be clearly resolved from the dermis (DR). In the dermal vasculature, bigger vessels appear mainly in red, whereas smaller vessels appear mainly in green. Psoriatic skin exhibits epidermal thickening, capillary elongation and increased dermal vascularization. Scale bars, 200 μm. Figure adapted from ref. 6, Macmillan Publishers Ltd.

Ntziachristos and colleagues' work is a clear step towards providing a benchmark technology for the non-invasive diagnosis of skin diseases. Further research that leverages the capabilities of UB-RSOM will most likely lead to the label-free identification of biomarkers for other skin conditions, potentially avoiding the need for invasive biopsies. And, as the authors showed for psoriasis, the technology could also enable the development of accurate severity indexes for other diseases. Another possible application for UB-RSOM is the study of skin health. The elasticity and trophism of reticular and deep dermis are essential to maintaining the skin in an optimal hydrated state. Furthermore, the high sensitivity of UB-RSOM and its capability to observe structures deep in the skin makes it an ideal tool for studying skin ageing, as well as for monitoring and evaluating the efficacy of cosmetic treatments.

References

  1. 1

    Ruocco, E., Baroni, A., Donnarumma, G. & Ruocco, V. Clin. Dermatol. 29, 548–556 (2011).

    Article  Google Scholar 

  2. 2

    Russo, T., Piccolo, V., Lallas, A. & Argenziano, G. F1000Research 5, 184 (2016).

    Article  Google Scholar 

  3. 3

    Edwards, S. J., Osei-Assibey, G., Patalay, R., Wakefield, V. & Karner, C. Clin. Exp. Dermatol. 42, 266–275 (2017).

    CAS  Article  Google Scholar 

  4. 4

    Lin, S. J., Jee, S. H. & Dong, C. Y. Eur. J. Dermatol. 17, 361–366 (2007).

    PubMed  Google Scholar 

  5. 5

    Kleinerman, R., Whang, T. B., Bard, R. L. & Marmur, E. S. J. Am. Acad. Dermatol. 67, 478–487 (2012).

    Article  Google Scholar 

  6. 6

    Aguirre, J. et al. Nat. Biomed. Eng. 1, 0068 (2017).

    Article  Google Scholar 

  7. 7

    Nestle, F. O., Kaplan, D. H. & Barker, J. N. Engl. J. Med. 361, 496–509 (2009).

    CAS  Article  Google Scholar 

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Correspondence to Antonio Costanzo.

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Narcisi, A., Favaro, R. & Costanzo, A. Diagnostic imaging: Listening in to skin disease. Nat Biomed Eng 1, 0076 (2017). https://doi.org/10.1038/s41551-017-0076

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