Novel Piezoelectric Amino-acid Ultrasound Transducer to Deliver Drugs Through the Blood Brain Barrier

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Abstract Neurodegenerative diseases and brain cancers are challenging to treat due to the presence of blood brain barrier (BBB), which is formed by tight junctions between endothelial cells in the microvasculature of the brain and prevents most of the therapeutics from access to the brain tissues. Among several reported approaches, ultrasound (US) has been demonstrated to be the most effective and safe method to facilitate the BBB opening. External US is however limited in efficacy to small animals whose skull bone is thin. In the case of humans, the thick skull bone absorbs more than 90% of US energy, requiring large and bulky arrays of external US transducers, which often consumes several hours of stimulation and requires tedious MRI monitoring during the sonication. Moreover, this extensive process is only useful for a single-time stimulation while research has shown the opening of BBB requires repetitive application of US. Implanted US transducers have thus emerged as an excellent alternative. Unfortunately, commercial US transducers rely on conventional piezoelectric materials, which contain toxic elements such as Lead in PZT (Lead Zirconate Titanate) and are non-degradable, therefore requiring invasive brain-surgery for removal. To overcome these problems, the PI’s group has recently developed a new biodegradable piezoelectric transducer, based on Poly-L-Lactide (PLLA). PLLA however has a modest piezoelectric constant and thus cannot generate a powerful US to open the BBB deep inside the brain tissue. Glycine, a biodegradable and safe amino acid, has been found to possess an extremely high piezoelectric constant, even comparable to that of piezoelectric ceramics like PZT. Unfortunately, glycine crystals are brittle and difficult-to-handle, rendering the material challenging to be used for high performance piezoelectric US transducer. Here, we propose a new strategy for material processing and device fabrication to (1) manufacture a biodegradable, flexible, easy-to-use, and highly piezoelectric nanofiber film of glycine crystals embedded inside a polycaprolactone (PCL) polymeric matrix and (2) employ this flexible glycine/polymer nanofibers to create a powerful US transducer which is implanted into the brain to facilitate drug-delivery through the blood-brain barrier (BBB) for the treatment of brain cancers. Our major hypothesis is that; the glycine-based ultrasound transducer will be able to provide a sufficient acoustic wave which can facilitate a safe and transient opening of BBB for the diffusion of anti-cancer drugs through the BBB to treat brain cancers. To demonstrate the hypothesis, we design the project with three specific aims. Aim 1 is to assess the piezoelectric performance, characterize the functional lifetimes, and evaluate acoustic field from the glycine/PCL transducer in vitro. Aim 2 is to asses safety (local and systemic toxicity) of the implanted transducer and the applied US in a large animal model. Aim 3 is to assess anti-tumor efficacy of the treatment using the implanted transducer + anti-cancer drugs in vivo.