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 ultrasound transducers have thus emerged as an excellent alternative that can be easily used to repeatedly induce low-intensity sonication deep inside brain tissue at a precise brain location. Indeed, a commercial ultrasound transducer, termed as SonocloudTM, has been clinically tested for brain implantation and shown a great potential to facilitate BBB drug-delivery without any US- induced damage to underlying brain tissue. Unfortunately, commercial transducers, including the Sonocloud, rely on conventional piezoelectric materials (mostly ceramics of PZT or Lead Zirconate Titanate), which contain toxic elements such as Lead and are non-degradable. The conventional US transducers therefore require invasive brain-surgery for removal, raising a significant safety concern. In this regard, the PI?s group has developed a new biodegradable and biocompatible piezoelectric material, based on a common medical polymer of Poly-L-Lactide (PLLA). We were also successful to employ the material for creating the first biodegradable ultrasonic transducer. Toward the end goal of using this novel transducer for BBB drug-delivery, here we propose to study the safety of this device for long-term implantation in the brain and assess the ability of the transducer to open the BBB, which then facilitates the delivery of drug models into the brain tissue. Our main hypothesis is that the transducer, made of common medical materials, which have been used extensively for many FDA-approved implants, will be highly biocompatible and eventually self-vanish to avoid invasive, surgical removal, while providing an excellent performance for BBB opening to deliver multi-sized drugs into the brain during its defined functional-lifetime. To demonstrate the premise, this proposal will have three different aims.
Aim 1 is to characterize the output acoustic pressure and functional lifetime of our biodegradable US transducer.
Aim 2 is to study long-term biocompatibility of the US transducer inside the rodent brain.
And Aim 3 is to assess BBB disruption (BBBD) and demonstrate the delivery of drug models into the brain tissue in vivo.
Neurodegenerative diseases and brain cancers are difficult to treat due to the presence of blood brain barrier (BBB), which prevents most of therapeutic drugs from penetrating the tight junctions of endothelial cells in the brain microvasculature and accessing the brain tissues. We have developed, for the first time, a biodegradable transducer which can be safely implanted into the brain to generate ultrasound (US) and induce BBB opening. Here we propose to (1) study the safety of this device for long-term brain implantation and (2) demonstrate the device?s capability to generate effective US for the BBB opening and facilitate the delivery of a drug-model with various sizes into the brain.
