Opening a window to skin biomarkers for diabetes stage with optoacoustic mesoscopy

Being the largest and most accessible organ of the human body,the skin could offer a window to diabetes-related complications on the microvasculature.However,skin microvasculature is typically assessed by histological analysis,which is not suited for applications to large populations or longitudinal studies.We introduce ultra-wideband rasterscan optoacoustic mesoscopy(RSOM)for precise,non-invasive assessment of diabetes-related changes in the dermal microvasculature and skin micro-anatomy,resolved with unprecedented sensitivity and detail without the need for contrast agents.Providing unique imaging contrast,we explored a possible role for RSOM as an investigational tool in diabetes healthcare and offer the first comprehensive study investigating the relationship between different diabetes complications and microvascular features in vivo.We applied RSOM to scan the pretibial area of 95 participants with diabetes mellitus and 48 age-matched volunteers without diabetes,grouped according to disease complications,and extracted six label-free optoacoustic biomarkers of human skin,including dermal microvasculature density and epidermal parameters,based on a novel image-processing pipeline.We then correlated these biomarkers to disease severity and found statistically significant effects on microvasculature parameters as a function of diabetes complications.We discuss how label-free RSOM biomarkers can lead to a quantitative assessment of the systemic effects of diabetes and its complications,complementing the qualitative assessment allowed by current clinical metrics,possibly leading to a precise scoring system that captures the gradual evolution of the disease.

Optoacoustic microscopy at multiple discrete frequencies

Optoacoustic(photoacoustic)sensing employs illumination of transient energy and is typically implemented in the time domain using nanosecond photon pulses.However,the generation of high-energy short photon pulses requires complex laser technology that imposes a low pulse repetition frequency(PRF)and limits the number of wavelengths that are concurrently available for spectral imaging.To avoid the limitations of working in the time domain,we have developed frequency-domain optoacoustic microscopy(FDOM),in which light intensity is modulated at multiple discrete frequencies.We integrated FDOM into a hybrid system with multiphoton microscopy,and we examine the relationship between image formation and modulation frequency,showcase high-fidelity images with increasing numbers of modulation frequencies from phantoms and in vivo,and identify a redundancy in optoacoustic measurements performed at multiple frequencies.We demonstrate that due to high repetition rates,FDOM achieves signal-to-noise ratios similar to those obtained by time-domain methods,using commonly available laser diodes.Moreover,we experimentally confirm various advantages of the frequency-domain implementation at discrete modulation frequencies,including concurrent illumination at two wavelengths that are carried out at different modulation frequencies as well as flow measurements in microfluidic chips and in vivo based on the optoacoustic Doppler effect.Furthermore,we discuss how FDOM redefines possibilities for optoacoustic imaging by capitalizing on the advantages of working in the frequency domain.