Pushing the limits of brain imaging: A new tool for targeted delivery of imaging agents and drugs

Multiphoton microscopy is a valuable tool for neuroscience research, allowing scientists to observe functional brain activity in real time through high-resolution imaging. An essential component of many multiphoton microscopy imaging studies is the delivery of chemical compounds, including imaging agents and drugs. However, many compounds cannot cross the blood–brain barrier and, therefore, cannot be delivered to the brain through systemic administration.

To address this issue, a team from Massachusetts General Hospital has developed a novel cannula delivery system that enables the effective administration of imaging agents and compounds during extended live (“in vivo”) imaging via multiphoton microscopy. The low-profile micropipette (“cannula”) is implanted at a shallow angle, as low as 8 degrees, nearly parallel to the brain's surface. As reported in Neurophotonics, this approach ensures that imaging agents can be delivered directly to the brain without obstructing the optical path for high-resolution imaging.

Corresponding author Steven Hou explains, "Many of the fluorescent sensors and reporters to study biological processes with optical imaging are not genetically encoded. Instead, imaging requires direct administration of fluorescent dyes into the brain, which normally precludes longitudinal imaging studies. We provide a rigorous approach to introduce a shallow angle, chronically implanted cannula for introduction of imaging agents into the brain during long-term in vivo imaging.”

To validate the effectiveness of this cannula delivery method, the team conducted several experiments. They successfully infused fluorescent cell markers into the brain while simultaneously imaging them using multiphoton microscopy. In addition, in mice modeling Alzheimer's disease, they tracked degenerating neurons using a special dye, Fluoro-Jade C, and performed long-term imaging of brain tissue oxygen levels using a phosphorescent oxygen sensor.

Neurophotonics Associate Editor Andy Shih of the Seattle Children's Center for Developmental Biology and Regenerative Medicine remarks, “The technique is a major step forward for mouse cranial imaging windows, which opens the way to better dye delivery and improved quality of imaging data.”

Although not completely noninvasive, this innovative technique could significantly enhance longitudinal studies on brain function, disease progression, and potential treatments, offering researchers more precise tools for their work for a wide range of new brain imaging applications.

To aid widespread adoption, the authors provide extensive detail on the construction and implantation of the cannula. For details, see the original Gold Open Access article by S. S. Hou et al., “Shallow-angle intracranial cannula for repeated infusion and in vivo imaging with multiphoton microscopy,” Neurophotonics 12(2), 025001 (2025), doi: 10.1117/1.NPh.12.2.025001.