A collaborative research group led by Professor Inki Kim (Department of Biophysics, Sungkyunkwan University), in partnership with Professors Byullee Park and Jong-Chan Park, has successfully developed a large-area volumetric photoacoustic microscopy (PAM) platform utilizing a metalens. This breakthrough enables unprecedented three-dimensional imaging of neuromelanin within brain organoids, with profound implications for the study of neurodegenerative diseases such as Parkinson’s disease.

Photoacoustic imaging is a hybrid modality that combines optical excitation with ultrasonic detection: pulsed laser light is delivered into biological tissue, where absorbed photons induce thermoelastic expansion and generate ultrasonic waves. While optical imaging suffers from severe scattering within tissue, ultrasound experiences minimal attenuation, permitting deeper penetration. Thus, PAM uniquely offers the synergistic advantages of optical-resolution imaging and ultrasonic depth reach, and has been actively applied in oncology, vascular studies, and metabolic research without the need for exogenous labels.

Conventional PAM, however, is constrained by the fundamental trade-off between resolution and depth of focus. As imaging departs from the optical focal plane, both signal strength and resolution rapidly decline, making label-free volumetric imaging of thick biological constructs such as organoids extremely challenging.

To overcome this limitation, the research team engineered a novel phase-controlled metalens capable of generating a non-diffracting needle beam. By merging phase maps corresponding to lenses of distinct focal lengths into a single titanium dioxide (TiO₂)-based metasurface, the group produced a lens that preserves diffraction-limited resolution while extending the depth of focus by more than 13.5-fold compared to conventional optics. This innovation, unachievable with traditional refractive lens designs, represents a transformative step in lens engineering.

The needle-beam metalens was subsequently integrated into a photoacoustic microscope, enabling high-resolution volumetric visualization of neuromelanin distribution within living brain organoids. Neuromelanin, a critical biomarker for Parkinson’s disease and other neurodegenerative disorders, has previously been inaccessible to quantitative imaging due to the optical opacity of brain tissue models. Using this platform, the team successfully captured three-dimensional maps of neuromelanin across forebrain and midbrain organoids, and experimentally demonstrated dynamic changes in melanin distribution as a function of culture duration. These findings hold direct significance for elucidating the pathological mechanisms of Parkinson’s disease, as disease onset and progression are strongly age-related.

According to Professor Kim: “Our metalens-based photoacoustic microscopy is not limited to brain organoids, but can be broadly applied to diverse classes of organoid systems. This technology thus provides a versatile tool for probing pathological mechanisms and assessing pharmacological efficacy across a wide spectrum of biomedical research domains.”

The study, entitled “Axially multifocal metalens for 3D volumetric photoacoustic imaging of neuromelanin in live brain organoid”, has been published in Science Advances (Impact Factor 12.5). The work was supported by the National Research Foundation of Korea (NRF) through the STEAM: Global Convergence Research Program, the K-Brain Project, the Sejong Science Fellowship, and the Young Investigator Program.

※ Title: Axially multifocal metalens for 3D volumetric photoacoustic imaging of neuromelanin in live brain organoid

※ Journal: Science Advances (IF: 12.5)

※ Link: https://doi.org/10.1126/sciadv.adr0654

▲Figure 1. Needle beam metalens with extended depth of focus and its application to brain organoid imaging

▲ Figure 2. Photoacoustic imaging of the 3D melanin distribution within a brain organoid using a needle beam metalens

▲ Figure 3. Metalens-based neuromelanin quantification for Parkinson’s disease research