UConn engineers have designed a non-toxic, biodegradable device that can help medication move from blood vessels into brain tissues – a route traditionally blocked by the body’s defense mechanisms.
They describe their invention in the December 23 issue of PNAS.
Blood vessels in the brain are lined by cells fitted together tightly, forming a so-called blood-brain barrier, which walls off bacteria and toxins from the brain itself.
But that blood-brain barrier also blocks medication for brain diseases such as cancer.
“A safe and effective way to open that barrier is ultrasound,” says Thanh Nguyen, a biomedical engineer at UConn. Ultrasonic waves, focused in the right place, can vibrate the cells lining blood vessels enough to open transient cracks in the blood-brain barrier large enough for medication to slip through.
But the current ultrasound technology to do this requires multiple ultrasound sources arrayed around a person’s skull, and then using an MRI machine to guide the person operating the ultrasounds to focus the waves in just the right place. It’s bulky, difficult, and expensive to do every time a person needs a dose of medication.
There is another way: implanted devices can apply ultrasound locally in the brain. It’s much more precise and repeatable, but most ultrasound transducers contain toxic materials such as lead.
And they have to be removed after use, which requires surgery and can harm brain tissue.
Nguyen knew there could be a better tool for this. His lab specializes in piezoelectric biomaterials. Piezoelectrics convert physical strain, such as being bent or compressed, into electricity, and vice-versa.
They are the perfect material for transducers, which use electricity to create vibration.
The same sensor can also act as an ultrasonic transducer. Image is credited to Thanh Nguyen.
Nguyen’s graduate student Eli Curry figured out how to spin poly L-lactic acid (PLLA), a biodegradable polymer, into tiny nano-fibers just 200 nanometers wide and several tens to hundreds of microns long.
When the researchers applied a high voltage during this spinning process, the fibers stretched and aligned.
Thus aligned, they could be woven into a mesh. And the alignment of the fibers heightened their piezoelectric response, allowing the nano-fiber PLLA to vibrate more powerfully using much less electricity than a regular film of the polymer would have.
These highly piezoelectric nanofibers enable the researchers to fabricate a sensitive biodegradable implanted sensor which can wirelessly measure intra-organ pressures. The same sensor can also act as an ultrasonic transducer.
Credit: Research Nguyen.
PLLA is often used for dissolving surgical sutures and is a very safe, bio-compatible material. Accordingly, when graduate student Thinh Le implanted the PLLA transducers into mice, he found that the transducers were safely biodegraded. Most significantly, the device can generate well-controlled ultrasound to locally open the blood-brain barrier, consequently helping medications injected into the blood access the brain tissue.
This ultrasound device can even act as an speaker to generate audible sound or play music.
Credit: Research Nguyen.
“This is an exciting proof of concept; it’s the first biodegradable transducer made of common and safe medical materials,” says Nguyen. He says the team still needs to work out how to optimize the intensity to get good cracks in the blood-brain barrier, wide enough for large drug molecules to pass through, without damaging the blood vessels or the brain. And for the device to be approved for use in humans, it would need to be tested for longer periods of time, in animals larger than mice.
Funding: The research was funded in part by a grant from the National Institutes of Health.
Decades of dedicated efforts have led to scientific advances in understanding the physiology of many diseases and development of a wide array of therapeutic materials. To fulfil their intended purpose, therapeutic materials must have adequate pharmacokinetics and pharmacodynamics that can allow them to accumulate in the diseased site in their therapeutically effective concentration.
Advances in the treatment of infections or malignancies residing in peripheral tissues are growing at a faster pace compared to their CNS-associated equivalents. In large part, this phenomenon is due to the inability of the therapeutic material to cross brain barriers from the systemic circulation into brain parenchymal tissues.
In this review, we describe the anatomical structure of brain barriers with a focus on the major contributor to the brain’s strict permeability. We review excerpts of CNS drug delivery approaches available for clinical use or still undergoing clinical or preclinical trials. We also highlight the principles underlying their mechanism of action and bring out some of their advantages and limitations. Finally, we attempt to follow their progress as they weave their way from preclinical investigation to clinical use.
Targeted drug delivery has found applications in the diagnosis and treatment of many diseases, such as cancer [1], diabetes [2] and neurodegenerative diseases [3].
As yet, neurodegenerative diseases remain an area where targeted drug delivery is most needed, since surgical treatments are not always an option and a treatment at a molecular level is needed. Additionally, intravenously injected neurotherapeutic materials not only have to evade en route biological barriers, such as solubility in the blood stream, stability against enzymatic degradation and phagocytosis, but also barriers interposed between the systemic circulation and brain tissues [4].
Barriers of the central nervous system (CNS) are made of specialized cells that lie at the interface between blood and nervous tissues, forming the blood-brain barrier (BBB), and between blood and cerebrospinal fluid, forming the blood-cerebrospinal fluid barrier (BCSFB) Figure 1 [5,6,7,8,9].
These specialized cells express transmembrane proteins with which they can seal off the intercellular space protecting brain tissues from micro-organisms, toxic compounds and fluctuations in the blood stream that can disrupt synaptic transmission allowing the brain to efficiently perform its vital functions [5,10].
The BBB is considered as the primary contributor to the brain’s strict permeability due to its larger surface area and its faster blood flow rate in comparison to BCSFB [8]. BBB cells are the endothelial cells that line brain vasculature, while BCSFB cells are the choroid plexus epithelium cells that line the cerebral ventricles and the arachnoid epithelium that line the brain vasculature in the subarachnoid space [5].
The three main barriers in the central nervous system (CNS), namely the meningeal or arachnoid barrier, the choroid plexus barrier and the blood brain barrier (BBB). The arachnoid and choroid plexus barriers separate the blood from the cerebrospinal fluid (CSF), and the BBB separates the blood from the interstitial fluid (ISF). At each site, the barrier is mainly formed by tight junctions that seal off the paracellular space. The blood brain barrier possesses an intricate architecture of basement membrane, mural and glial cells that work in synergy to maintain the barrier’s integrity and regulate its permeability in response to neuronal needs.
Microbubble-Assisted Focused Ultrasound Irradiation (MB-FUS)
Image-guided focused ultrasound (FUS) emerged as an alternative approach for the induction of transient BBB disruption after it had for been tested for a long time as a non-invasive thermal ablation technique for the treatment of brain tumors [56,57,58].
Early investigations of FUS-induced BBB disruption and its bioeffects on brain tissue reported the occurrence of tissue damage that manifested itself as lesions or necrosis due to exposure to high frequencies of FUS [59,60,61,62,63]. Intravenous injection of preformed microbubbles prior to FUS exposure prevented tissue damage by attenuating the effective FUS power levels [64,65,66,67].
The microbubbles, which are typically commercially accessible lipid or albumin shells encapsulating gaseous material, such as Optison, harness the acoustic power and concentrate it to the blood vessel walls maximizing its efficiency, and thus, lowering the threshold of effective power levels (Figure 9) [64,65,66,67].
Circulating micro-bubbles move in the direction of the FUS wave propagation and are brought in close contact with the vessel’s ECs [64,65,66,67]. Depending on their size and the acoustic power level, microbubbles can oscillate, micro-streaming the medium surrounding them, expand, or collapse, exerting mechanical stress on ECs, modifying their membranes and the tight junctions between them [64,65,66,67].
The transient disruption induced by microbubble-assisted FUS lasts for a short period of time, from 4 to 6 h, the length of which can be modulated by tuning pulse duration, pulse frequency, exposure time and microbubbles’ diameter [64,65,66,67].
The success of trans-BBB delivery following a microbubble-assisted FUS BBB-disruption event was demonstrated for a broad spectrum of therapeutic materials, including liposome-encapsulated and antibody-based anticancer agents [64,68,69].
Orthogonal techniques, such as magnetic resonance imaging (MRI), have been used to visualize and monitor the process in real-time to ensure adequate optimization of the BBB disruption parameters and deep tissue targeting with efficient spatial resolution [64,65,66,67]. Minimizing aberrations in the phase and amplitude of FUS waves caused by the skull acoustic impedance remains the major challenge of this approach [64,70].
Correction for FUS beam aberrations introduced by the skull, whose thickness varies amongst species, requires determination of the acoustic properties of the test subjects’ skull. This can be achieved by CT scanning, and integrating the resulting data in aberration correction algorithms [64,70]. Correction of abrasions, together with the multiple MRI acquisitions and analysis, makes this approach time consuming, and considering the amounts of both ultrasound and MRI contrast agents, may not always be cost-effective.
Principle of BBB disruption using MRI-guided microbubble-assisted focused-ultrasound technique (MB-FUS). (A) The patient’s head is rested in a semi-spherical ultrasound transducer integrated into an MRI scanner. The transducer is attached to a mechanical positioning system. The focused ultrasound and the magnetic resonance parameters are remotely controlled by electronic interfaces. The patient’s head is immobilized by a stereotactic frame. Overheating of the scalp, skull and brain tissue is minimized by the use of a water interface, which also acts as an acoustic coupler. (B) Pretreatment of the patient with microbubbles harnesses the acoustic power and concentrates it to the blood vessel, which attenuates acoustic power levels. Microbubbles move in the direction of the FUS wave propagation and under the influence of the FUS waves they oscillate, micro-streaming the medium surrounding them, inducing mechanical stress that disrupts the TJs between ECs. Figure 9 (A) adapted from Martin et al. [57].
The mechanism by which TJs protein impairment is evoked, including how hyperosmotic or mechanical stress contribute to this impairment, remains unknown. In independent studies, immunoelectron microscopic examination after hyperosmotic and FUS-induced disruption showed both redistribution and loss of immunosignals of TJ proteins in affected brain regions [67,71]. Loss of immunosignals can be attributed to disint
The major concern in transient BBB disruption technologies is that during the therapeutic window, the CNS remains unprotected against blood-borne toxins, such as bacteria and viruses, and blood components that are considered neurotoxic. Therefore, the technique requires careful planning, monitoring and optimization of the therapeutic window to ensure optimal therapeutic efficacy and reduced side effects.
Source:
University of Connecticut
Media Contacts:
Ian Hamilton & Sally Marlow – University of Connecticut
Image Source:
The image is credited to Thanh Nguyen.
Original Research: Closed access
“Biodegradable nanofiber-based piezoelectric transducer”. Thanh Nguyen et al.
PNAS doi:10.1073/pnas.1910343117.
