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Department of Bioengineering, Clemson University, Clemson, SCDepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC
Laser speckle contrast imaging, or laser speckle imaging (LSI), is a noninvasive imaging technology that can detect areas of dynamic perfusion or vascular flow. Thus, LSI has demonstrated increasing diagnostic utility in various pathologies and has been employed for intraoperative, postoperative, and long-term monitoring in many medical specialties. Recently, LSI has gained traction in clinical dermatology, as it can be effective in the assessment of pathologies that are associated with increased perfusion and hypervascularity as compared to normal tissue. To date, LSI has been found to be highly accurate in monitoring skin graft reperfusion, determining severity of burns, evaluating neurosurgical revascularization, assessing persistent perfusion in capillary malformations post-laser therapy, and differentiating malignant and benign skin lesions. LSI affords the advantage of non-invasively assessing lesions prior to more invasive methods of diagnosis, such as tissue biopsy, while remaining inexpensive and exhibiting no adverse events to date. However, potential obstacles to its clinical use include tissue movement artifact, primarily qualitative data, and unclear impact on clinical practice given lack of superiority data compared to current standard of care (SOC) diagnostic methods. In this review, we discuss the clinical applications of LSI in dermatology for use in the diagnosis and monitoring of vascular, neoplastic, and inflammatory skin conditions.
LASER SPECKLE IMAGING:
Laser speckle imaging (LSI), first introduced in 1981, is recognized as a convenient method for visualizing blood flow within vessels. LSI often utilizes a low-intensity near-infrared laser, a low-power and long-wavelength light source, to illuminate the skin. Light is reflected towards the device’s sensor to provide information about blood flow over time, which is then captured by a camera. The image’s resulting pixel pattern, known as speckles, is subsequently analyzed by computer software to quantify movement of these pixels. Laser speckles occur when a coherent light illuminates a surface, producing random interference effects. Such light is often from a laser beam of a particular wavelength. In the LSI skin imaging, the light source is often a continuous wave laser running at near-infrared region (e.g., 785 nm), the so-called therapeutic window, where light can penetrate better and dispose less energy to tissue compared with visible or infrared light. The resulting laser speckle interference effect is displayed visually as a granular pattern consisting of dark and bright spots. When the speckle pattern is illuminated on a moving object, such as in-transit intravascular fluid, the flow disturbs the speckle pattern causing blurriness of laser speckles, causing partial or complete disappearance of speckles in the image of the flow related region. LSI captures this speckle displacement, creating a quasi-real time blood flow imaging system [Figure 1] (
). LSI images can be analyzed using spatial and temporal analysis, both of which are demonstated in Figures 2 and 3. Spatial analysis, or laser speckle contrast analysis (LASCA), requires only one image and measures contrast in that image over pixels. Temporal analysis requies a series of multiple images and measures contrast in one pixel over the sequential images. The temporal method affords better spatial resolution, as it uses single-pixel intensity over a period of time.(
). LSI has been effectively translated into medicine for the purpose of monitoring revascularization, particularly in the fields of neurosurgery and ophthalmology (
). In a recent review of all clinical applications of the technology, no adverse events were reported, most likely due to LSI’s low photon energy and illumination power (
Figure 1Cartoon rendering laser speckle imaging (LSI) device function. (1) Low-intensity, near-infrared coherent light illuminates skin surface with a targeted lesion. (2) Light is reflected towards the device sensor, allowing information about blood flow over time to be captured by the camera. (3) Granular pixel pattern is analyzed using ImageJ or MATLAB software.
Figure 2Laser speckle images in “normal” versus lesional skin in a patient with biopsy-proven melanoma. The x- and y-axes represent pixel positions, and the color maps indicate the value of K, the local spatial variance or speckle contrast. Areas with higher blood flow have a lower contrast, or K. All images were captured with a laser wavelength of 785 nanometers and a circular aperature 2 centimeters in diameter. Spatial correlation was captured over 7 x 7 pixels, and temporal correlation was analyzed over 49 images. (a) Left panel: Laser speckle images captured over “normal” skin in a patient seen in a dermatology clinic at the Medical University of South Carolina. Imaging of normal skin resulted in homogenous laser speckle pattern. (b) Right panel: Laser speckle images captured in the same patient over a lesion concerning for cancer, confirmed with biopsy to be malignant melanoma. Imaging of melanoma demonstrates higher blood flow around the lesion periphery compared to the center of the lesion in temporal correlation, as well as compared to the control skin in (a). Spatial and temporal images are similar with improved spatial resolution reflected in the temporal correlation.
Figure 3Laser speckle images in “normal” versus lesional skin in a patient with a cherry angioma. As in Figure 2, the x- and y-axes represent pixel positions, and the color maps indicate the value of K, the local spatial variance or speckle contrast. Areas with higher blood flow have a lower contrast, or K. All images were captured with a laser wavelength of 785 nanometers and a circular aperature 2 centimeters in diameter. Spatial correlation was captured over 7 x 7 pixels, and temporal correlation was analyzed over 49 images. (a) Left panel: Laser speckle images captured over “normal” skin. Again, imaging of normal skin resulted in homogenous laser speckle pattern. (b) Right panel: Laser speckle images captured in the same patient over a stable cherry angioma. Imaging of cherry angioma demonstrates overall higher blood flow compared to control skin, with pinpoint areas of highest blood flow within clumped lesional blood vessels, best appreciated in spatial correlation. Temporal correlation depicts less change in speckle contrast over time compared to the contrast over one image using spatial correlation.
LSI is a technology with both clinical and surgical dermatologic utility. LSI is effective for evaluating vascular anomalies, cutaneous neoplasms, inflammatory dermatoses, autoimmune conditions, and dermal and subcutaneous growths through detection of perfusion differences in lesional versus perilesional skin. This imaging method has also proven to be an effective surgical tool for the planning of skin graft dissections, as well as the assessment of revascularization of skin grafts and flaps after surgery (
). Dermatologic advantages of LSI include its noninvasive nature, low cost, rapid results, and ability to produce accurate data when used simultaneously with dermoscopy (
). The purpose of this review is to highlight applications of LSI in clinical dermatology. Selected studies involve investigation of the utility and efficacy of LSI for diagnostic or management purposes of three major categories of dermatologic lesions: vascular, neoplastic, and inflammatory.
Vascular Anomalies
A capillary malformation, known as a nevus flammeus or port wine stain (PWS), appears clinically as a red-purple patch present from birth. Port wine stains are often benign birthmarks but have recently been found to be associated with high-morbidity genetic syndromes such as Sturge-Weber and Klippel-Trénaunay-Weber when present with more widespread vascular malformations (Fitzpatrick, 2018,
). Treatment with pulsed dye laser (PDL) is the SOC approach to these congenital lesions; however, complete resolution with PDL is not commonly achieved.
Huang, et al. were the first to describe the use of LSI as a tool for assessment of perfusion changes during and after treatment of port wine stains with PDL. Though the study showed an overall decrease in perfusion of lesions after treatment, and many speckle maps indicated areas within lesions that maintained some degree of persistent perfusion. The authors hypothesized that this persistent, undesired blood flow represented regions that received incomplete PDL therapy and suggested that increased use of real-time LSI during laser treatments could result in more thorough treatment and improved removal of PWS lesions in the future (
Additional studies have since drawn similar conclusions and shown the efficacy of LSI as a noninvasive method of post-treatment monitoring of PWS birthmarks. Qiu, et al., noted that the superior ability of LSI to detect microvascular blood flow changes over both space and time is a feature not afforded with lesional biopsies (
In a report of a 7-month-old infant with a magnetic resonance imaging (MRI)-confirmed arteriovenous malformation (AVM), LSI technology was used to further characterize the lesion. The authors found that LSI accurately highlighted the lesion in a similar pattern as MRI. They suggest that LSI could be preferable for initial AVM assessment in patients with contraindications to MRI or in pediatric patients due to the lack of anesthesia required to obtain imaging (
Literature detailing use of LSI for assessment of other vascular anomalies, such as venous or lymphatic malformations, is scarce, and thus further studies are required to assess efficacy of LSI as a diagnostic and post-treatment monitoring tool of vascular malformations as compared with current SOC imaging modalities.
Skin Cancers
Tissue biopsy is the gold standard of diagnosis for skin malignancies, but this can occasionally result in unnecessary, invasive diagnostic measures in patients who are ultimately proven to have a benign skin condition (
). Biopsy procedures have inherent risks of bleeding, infection, scarring, and disfiguration, thus assessment of suspicious skin lesions with a noninvasive modality prior to skin biopsy might decrease the rate of unnecessary procedures, as well as procedure-related complications.
LSI has been shown to be an accurate tool in differentiating benign and malignant skin lesions. Tchvialeva, et al., utilized LSI to assess five different types of benign and malignant skin lesions in vivo: basal cell carcinoma (BCC), squamous cell carcinoma (SCC), malignant melanoma (MM), seborrheic keratosis (SK), and melanocytic nevus (
). Malignant diagnoses were confirmed with tissue biopsy. A total of 214 skin lesions were analyzed using two different wavelengths: red laser (663 nm), which differentiates SK from MM, BCC, and nevus, and blue laser (407 nm), which differentiates the speckle pattern of MM from SK, BCC, and SCC. Accuracy was assessed using receiver operator characteristic (ROC) analysis compared to other diagnostic methods, including Raman spectroscopy, SIAscope, multispectral imaging, SolarScan, specialized dermatologists, general dermatologists, and general practitioners. LSI was shown to have similar accuracy as Raman, SIAscope, SolarScan, and expert dermatologists and higher accuracy as compared to general practitioners, general dermatologists, and multispectral imaging. When plotted on a ROC curve of sensitivity against 1-specificity, the area under the curve (AUC) measurements for red and blue lasers were 0.87 and 0.84, respectively (
). This study suggests that LSI is a high-accuracy, non-invasive strategy for assessing skin lesions suspicious for malignancy prior to invasive tissue sampling.
Another proof-of-concept study was conducted by Zieger, et al., in which nine patients with biopsy-confirmed BCCs were assessed with LSI to determine whether microvascular tumor blood flood differed from that of the perilesional skin. Speckle patterns were characterized by speckle size, speckle contrast, and fractional dimension. Results showed that using two specific wavelengths, 450 nm (blue region of spectrum) and 515 nm (cyan region), speckle patterns demonstrated statistically significant differences in lesional blood flow as compared to perilesional skin (p ≤.05 for speckle contrast (515 nm), ≤.01 for speckle size (515 nm), ≤.001 for fractional dimension (515 nm); no p-values specified for data at 450 nm). This study demonstrated that LSI is a reliable method for reproducibly assessing neoplasms of uncertain behavior compared to normal skin in a non-invasive manner. The authors suggest that tumor margins may also be detectable using LSI technology (
), which could be utilized during future surgical excisions.
At the Medical University of South Carolina, a customized LSI device has been built and used for lesions concerning skin cancer prior to tissue biopsy. The initial results demonstrated increased perfusion in lesional skin of neoplastic lesions, as well as bening vascular lesions (Figures 2 and 3). Given the scarcity of literature analyzing LSI’s efficacy in the diagnosis of skin malignancies, further studies are warranted to explore LSI for this application.
Inflammatory Conditions
Blood flow imaging by LSI can be used to evaluate inflammation and erythema by quantitatively measuring the velocity and hemoglobin content in capillaries of the skin (
), including those mediated by histamine. This may be translated to characterize inflammatory dermatologic conditions associated with increased blood flow or extravasation,(
) or to assess the effectiveness of treatment interventions utilizing therapies that have effects on blood flow, such as antihistamines and capsaicin (
). Overall, these studies suggested LSI holds potential to objectively assess signs of acute and chronic inflammation on the skin surface, such as in psoriasis and other inflammatory dermatoses.
Psoriasis
Skin microvasculature changes are implicated in the pathogenesis of psoriasis and correlate with increased lesion perfusion. In a 2021 pilot study, Schapp, et al. utilized the Handheld Perfusion Imager, a device powered by LSI, to examine microvascular skin perfusion in six adult patients with unstable plaque psoriasis, as defined by recent expansion of psoriatic plaques. In a total of 110 lesions, the LSI device was employed to evaluate perilesional perfusion and perfusion inhomogeneity as a way of predicting psoriatic lesion expansion (
). Results of a mixed multinomial logistic regression model demonstrated increased perilesional perfusion was predictive of psoriatic plaque expansion after two weeks as compared to lesion stability (OR 9.90; p-value<0.001; 95% Confidence Interval (CI) [4.61-21.28]) and lesion reduction (OR 10.85; p-value < 0.001; 95% CI [4.80-24.52]). Perfusion inhomogeneity was a weaker, but still statistically significant, predictor of lesion expansion at two weeks as compared to stability (OR 2.39; p-value=0.027; 95% CI [1.11-5.14]). From these results it was concluded that LSI has potential applications in assessing stable, improving, or expanding disease course in patients with psoriasis. However, further studies are required to determine specific uses in clinical practice (
Patients with systemic lupus erythematosus (SLE) are known to have alterations in both macro- and micro-circulation; thus, a 2021 study evaluated skin microvascular function in patients with SLE using LSI. The investigators found that patients with SLE exhibited blunted microvascular reactivity during reperfusion periods as compared with healthy controls, even in the absence of cardiovascular (CV) disease or CV risk factors (
). In addition to the dermatologic uses afforded by recognition of increased perfusion as previously described, LSI has also been shown to discern differences in skin surface roughness, making it a potential tool in the non-invasive assessment of skin cancers. In a study with sixty female volunteers, skin roughness of normal skin was assessed with LSI and the PRIMOS device, which creates a high-resolution and three-dimensional image of the skin surface. The study demonstrated that LSI was able to detect a significant difference in skin roughness across age groups, although not quite to the degree of the PRIMOS technology. The authors propose that the ability of LSI to measure skin roughness will have substantial clinical applications, such as detecting pre-cancerous skin lesions, which are often associated with increased skin roughness (
). In the future, LSI may be used for the objective assessment of cutaneous allergic reactions. LSI has also been shown to detect decreased perfusion in digital ulcers of systemic sclerosis patients (
Vanhaecke A, Schonenberg-Meinema D, De Schepper S, Bergkamp SC, Leone MC, Middelkamp-Hup MA, et al. Rarities in rare: illuminating the microvascular and dermal status in juvenile localised scleroderma. A case series. Clin Exp Rheumatol. 2022;40 Suppl 134(5):12-18.
). Additional research is needed to investigate whether these conditions may represent areas of future clinical utility for LSI.
Limitations
Although LSI remains an up-and-coming tool for the non-invasive assessment of skin lesions with increased vascularity, several limitations to its clinical use exist. The technology can have significant movement artifact, particularly when used via handheld device, which may require correction. (
) This could potentially limit use of the imaging in pediatrics or other populations that may have difficulty remaining motionless during assessment. There is also evidence of multiple scattering of speckles with LSI, which necessitates calibration. (
), and investigators have used different algorithms or measurements to assess speckle pattern changes objectively within the discussed studies. A consensus on the most accurate method of objectively quantifying image differences would be beneficial. Finally, given that many of the dermatologic conditions discussed are diagnosed either clinically or with established SOC diagnostic tests, it is unclear how LSI would change the scope of clinical practice for the management of these conditions, particularly without diagnostic superiority data compared to current diagnostics. It is the authors’ opinion that LSI’s utility in providing a means of monitoring lesions during or after treatment is a promising application of the technology.
CONCLUSIONS:
LSI has shown promise as a non-invasive, accurate method of diagnosing and monitoring multiple dermatologic pathologies, including vascular, neoplastic, and inflammatory skin conditions (Table 1). Additional benefits of the imaging modality include low cost and lack of adverse effects. However, some limitations of the technology exist, and most clinical studies of LSI in dermatology are limited to single lesion types with small patient populations. Future studies with larger sample sizes are necessary to further assess the clinical utility of this technology.
Table 1Summary of potential clinical uses of laser speckle imaging (LSI) in dermatology.
Dermatologic Diagnosis
Potential uses of LSI
Vascular Anomalies
Port wine stains
Monitoring of treatment success in lesions after pulsed dye laser (PDL) therapy Real-time assessment of lesions during PDL therapy
Arteriovenous malformations
Initial imaging assessment, without requirement for anesthesia in children
Venous and lymphatic malformations
Potential for initial imaging assessment, without requirement for anesthesia in children; further studies needed
Neoplastic Lesions
Skin cancers
Initial imaging assessment of lesions concerning for malignancy prior to invasive tissue biopsy, specifically differentiating malignant melanoma from other benign nevi or non-melanoma skin cancers Tumor margin assessment during surgical excisions
Inflammatory Conditions
Psoriasis
Prediction of disease progression/treatment response (stable, improving, or expanding)
Vanhaecke A, Schonenberg-Meinema D, De Schepper S, Bergkamp SC, Leone MC, Middelkamp-Hup MA, et al. Rarities in rare: illuminating the microvascular and dermal status in juvenile localised scleroderma. A case series. Clin Exp Rheumatol. 2022;40 Suppl 134(5):12-18.
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