Bypassing the blood-brain barrier in the non-invasive limit assisted by an optical fiber delivering picosecond infra-red laser pulses at O-H bond resonance

In the battle to treat neurodegenerative diseases, the blood-brain barrier presents a major bottleneck for reliable drug delivery. Low-intensity focused ultrasound has proven to be an effective method in transient barrier opening [1]. Convection-enhanced delivery (CED) is also pursued due to its simplicity, and the fact that unlike with methods that seek to increase the barrier permeability, it electively targets a specific brain area whereby reducing the drug dose and odds of undesired exposure to other organs [1]. Scar and bleeding, back-flow, and leakage are, however, chief among the drawbacks of CED [2] and have severely limited clinical translation. We propose a novel site-selective drug delivery technique facilitated by pathway creation using a sapphire optical fiber delivering pulses from a Picosecond Infra-Red Laser (PIRL). Histological analysis of murine brain revealed that in contrast with cannula insertion, the PIRL approach can accomplish scar-free access for drug injection with minimal amounts of bleeding when the pulse energy, repetition rate, and fiber insertion speed are chosen properly, leading to a smaller external force on tissue than with cannula or laser-off condition. A syringe pump enabled sub-μL precision and ultrasound imaging aided visualization of the process. The underlying physics is ultrafast energy absorption in tissue at O-H bond stretch resonance wavelength near 3 μm that strongly drives phase transitions, liquifying the tissue in the process [3].

[1] K. Piper, J. I. Kumar, J. Domino, Ch. Tuchek, M. A. Vogelbaum, “Consensus review on strategies to improve delivery across the blood-brain barrier including focused ultrasound”, Neuro-Oncology 26 (2024).

[2] F. Casanova, P. R. Carney, M. Sarntinoranont, “Effect of needle insertion speed on tissue injury, stress, and backflow distribution for convection-enhanced delivery in the rat brain”, PLOS ONE 9 (2014).

[3] S. Amini-Nik, D. Kraemer, M. L. Cowan, K. Gunaratne, P. Nadesan, B. A. Alman, R. J. D. Miller, “Ultrafast Mid-IR laser scalpel: Protein signals of the fundamental limit to minimally invasive surgery”, PLOS ONE 9 (2010).