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Skin is the largest organ and also the first barrier of body. Skin diseases are common, and cutaneous microcirculation is relative to various diseases. Researchers attempt to develop novel imaging techniques to obtain the complex structure, components, and functions of skin. Modern optical techniques provide a powerful tool with non-invasiveness, but the imaging performance suffers from the turbid character of skin. In vivo skin optical clearing technique has been proposed to reduce tissue scattering and enhance penetration depth of light and became a hot topic of research. The aim of this review is to provide a comprehensive overview of recent development of in vivo skin optical clearing methods, how in vivo skin optical clearing enhances imaging performance, and its applications in study and light therapy of various diseases. Based on the references published over the last decade, the important milestones on the mechanism, methods, and its fundamental and clinical applications of in vivo skin optical clearing technique are provided. With the deepening understanding of skin optical clearing mechanisms, efficient in vivo skin optical clearing methods were constantly screened out. These methods have been combined with various optical imaging techniques to improve imaging performances and acquire deeper and finer skin-related information. In addition, in vivo skin optical clearing technique has been widely applied in assisting study of diseases as well as achieving safe, high-efficiency light-induced therapy. In the last decade, in vivo skin optical clearing technique has developed rapidly and played an important role in skin-related studies. [ABSTRACT FROM AUTHOR]

To realize visualization of the skin microvascular dysfunction of type 1 diabetic mice, we combined laser speckle contrast imaging and hyperspectral imaging to simultaneously monitor the noradrenaline (NE)-induced responses of vascular blood flow and blood oxygen with the development of diabetes through optical clearing skin window. The main results showed that venous and arterious blood flow decreased without recovery after injection of NE; furthermore, the decrease of arterious blood oxygen induced by NE greatly weakened, especially for 2- and 4-week diabetic mice. This change in vasoconstricting effect of NE was related to the expression of α1-adrenergic receptor. This study demonstrated that skin microvascular function was a potential research biomarker for early warning in the occurrence and development of diabetes. The in vivo skin optical clearing method provides a feasible solution to realize visualization of cutaneous microvessels for monitoring microvascular reactivity under pathological conditions. In addition, visual monitoring of skin microvascular function response has guiding significance for early diagnosis of diabetes and clinical research.

Tissue optical clearing (TOC) is helpful for reducing scattering and enhancing the penetration depth of light, and shows promising potential in optimizing optical imaging performances. A mixture of fructose with PEG-400 and thiazone (FPT) is used as an optical clearing agent in mouse dorsal skin and evaluated with OCT angiography (Angio-OCT) by quantifying optical properties and blood flow imaging simultaneously. It is observed that FPT leads to an improved imaging performance for the deeper tissues. The imaging performance improvement is most likely caused by the FPT-induced dehydration of skin, and the reduction of scattering coefficient (more than ∼ 40.5%) and refractive-index mismatching (more than ∼ 25.3%) in the superficial (epidermal, dermal, and hypodermal) layers. A high correlation (up to ∼ 90%) between the relative changes in refractive-index mismatching and Angio-OCT signal strength is measured. The optical clearing rate is ∼ 5.83 × 10(-5) cm/s. In addition, Angio-OCT demonstrates enhanced performance in imaging cutaneous hemodynamics with satisfactory spatiotemporal resolution and contrast when combined with TOC, which exhibits a powerful practical application in studying microcirculation.

Hair follicle offers an excellent model for systems biology and regenerative medicine. So far, the stages of hair follicle growth have been evaluated by histological examination. In this work, a noninvasive spectroscopy was proposed by measuring the diffuse reflectance of mouse skin and analyzing the melanin value. Results show that the skin diffuse reflectance was relatively high when hair follicles were at the telogen stage and at the beginning of the anagen stage, and decreased with the progression of the anagen stage. When the hair follicle entered into the catagen stage, the diffuse reflectance gradually increased. The changes in the melanin content of skin had contrary dynamics. Substages of the hair follicle cycle could be distinguished by comparing the changes in melanin value with the histological examination. This study provided a new method for noninvasive evaluation of the hair follicle stage, and should be valuable for basic and therapeutic investigations on hair regeneration.

The high incidence and mortality of breast cancer requires an effective, rapid, and cost-effective method for its diagnosis. Here, visible and near-infrared spectroscopy in the wavelength range of 400 to 2200 nm is utilized for distinguishing the malignant tumor tissue from benign tumor and normal breast tissues. Based on the absorption and scattering spectra of fixed samples, three spectral analysis methods are proposed which include an absorption spectral analysis, a scattering spectral analysis, and a combined spectral analysis of the two. By comparison with the histopathological examination, the sensitivity, specificity, and accuracy of the three analysis methods are calculated. The results showed that the combined spectral analysis method can significantly enhance the effectiveness when compared with the sole absorption or scattering spectral analysis method. The sensitivity, specificity, and accuracy of the combined spectral analysis method are 100%, 87.82%, and 87.50% for the benign tumor tissue and 81.82%, 100%, and 87.5% for malignant tumor tissue, respectively. All of the three values are 100% for normal breast tissue. This study demonstrates that the combined spectral analysis method has better potential for in vitro optical diagnosis for breast lesions.

Optical imaging techniques have shown tremendous potential for assessing cutaneous microcirculation, but the imaging depth and contrast is limited by the strong scattering of skin. Current skin windows have to be fulfilled by surgical operation and suffer from some side effects. In this study, a switchable skin window was developed by topical application of an optical clearing agent (OCA) and saline on rat skin in vivo. The validity of the skin window was evaluated by the laser speckle contrast imaging technique, and the safety of OCA to the body was tested through histologic examinations. The results indicated that administration of OCA or saline on rat skin in vivo can open or close the window of skin repeatedly for three days. With the repair effect of hyaluronic acid and Vaseline, it is able to repeatedly visualize the dermal blood vessels and flow distribution. Long-term observation shows that there is no abnormal reflection in micro-structure, body weight, organ coefficients, histopathologic lesions, or toxic reactions compared with a control group. This switchable window will provide an effective tool not only for cutaneous microcirculation with laser speckle contrast imaging, but also for diagnosis and treatment of peripheral vascular diseases, including tumor research with various optical imaging techniques.