Various neurological disorders, from Parkinson’s disease to major depression, are treated using drugs that are delivered systematically, ultimately affecting tissues throughout the body indiscriminately. To avoid the inevitable side effects of these drugs, researchers are developing implantable devices that deliver drugs locally to the brain and nervous system. In a step forward, an international team of researchers has developed an implantable microfluidic ion pump system that can deliver large amounts of drugs to the brain with a low voltage and exceptionally high on-off ratio. In preliminary in vivo experiments in rats, which were described recently in Advanced Materials (doi:10.1002/adma.201701217), the researchers showed that the device could effectively alter the state of the brain.
“It’s a hybrid technology between a convection-enhanced delivery device and an ion pump,” says study lead author George Malliaras of France’s École Nationale Supérieure des Mines, referring to two approaches for localized cortical drug delivery. “Our main achievement was to take an ion pump device, which is very promising for drug delivery, and to make it practical.”
Convection-enhanced delivery devices, or CEDs, use high pressure to deliver drugs with intracranial needles or catheters. Though the fluid-delivery systems can bypass the blood-brain barrier and deliver high local drug concentrations, they increase the local pressure around the target area, potentially deforming tissue and causing neural damage. An alternative platform for cortical drug delivery is the organic electronic ion pump (OEIP), which transports ions from a source solution to a target solution (within the brain) through a selective ion bridge such as a polyelectrolyte film. Unlike CEDs, OEIPs use dry delivery—only the drug and not the solution is delivered—and do not require high pressure. However, because the ion bridge that connects the drug reservoir outside the body to the target in the skull is a centimeter long, OEIPs require voltages of tens of volts to deliver adequate amounts of drugs, leading to possible harmful electrolysis of the brain, Malliaras says.
Microfluidic ion pump system placed on the surface of a rat’s cortex. Image courtesy of George Malliaras/Advanced Materials.
To get around the limitation of OEIPs, Malliaras and his colleagues sought to combine a microfluidic system with an ion pump. The resulting microfluidic system would bring the drug molecules close to the delivery point, where they are pumped to the target area through small holes coated with ion bridge material. The microfluidic channel acts as a passive drug reservoir, and for fully implantable applications, this channel can be replenished as needed using a connected subcutaneous reservoir that is refilled with a syringe—a design similar to some CEDs.
The device is made up of two parylene sheets that are held together with medical-grade, double-sided adhesive tape, forming the microfluidic channel. The bottom parylene sheet layer contains a poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) electrode that traces the bottom of the microfluidic channel. The team created this part of the device by depositing a 3-µm-thick parylene film onto a 1-inch by 3-inch glass slide, then depositing a 10-nm-thick layer of Cr and 100-nm-thick layer of Au, and finally patterning the interconnects using a metal liftoff process with acetone. The slide was then patterned with PEDOT:PSS to form electrodes. The top half of the device required depositing a 1.7-µm-thick parylene film onto a glass slide, followed by patterning with Cr/Au, depositing a second 1.8-µm-thick parylene film layer, etching with AZ9260 photoresist to define the outline of the ion bridge pattern (300 through-holes for the in vivo version of the device), and patterning the ion bridge material (chemically bleached PEDOT:PSS). They sandwiched the layers with the adhesive, which was cut to the shape of the fluidic channel.
The researchers conducted a number of in vitro tests on their device using GABA, a neurotransmitter that scientists have used to control epileptic activity in in vitro models using OEIPs. The researchers measured the current flow through the ion bridge material and found that GABA accounted for 91% of the (cation) charge transport. The rest of the ions transported came from the solution, Malliaras says, adding that the amount of these ions is too low to cause any ill effects in real-world applications. The device showed a nearly 20-fold increase in the flux for GABA at only 1/20th of the voltage of previous reports of traditional OEIPs. And its on-off ratio was exceptionally high—nearly five orders of magnitude between 1 V and 0 V. In in vivo tests, which were done mostly to prove the device could be implanted, Malliaras and his team placed the device on the surface of a rat’s cortex and filled the microfluidic channel with KCl solution to deliver potassium ions. They found that they could induce hyperactivity within a matter of seconds.
Daniel Simon, a materials scientist at Linköping University in Sweden who researches cortical drug delivery using OEIPs, was impressed with the work, particularly the team’s successful merging of the mixed ionic and electric conduction of organic electronics and the easy long-range liquid transport of fluidics. “Indeed, I see their system as a great addition to the organic bioelectronics toolbox, showing the potential of hybrid solutions to the drug delivery challenge,” he says. But Simon, who was not involved in the work, doubts the electrolysis danger of traditional OEIPs, as well as the ability of the new microfluidic platform to sustain drug delivery for more than a couple seconds. Still, he looks forward to the team’s follow-up research. “And possibly combining their work with our own to overcome the last remaining hurdles in fast, efficient, sustainable, and leak-proof drug delivery components,” he says.
Malliaras and his colleagues are now using the platform in animal models of epilepsy to examine whether the microfluidic device can safely and effectively treat seizures. Other potential applications include subcutaneous implantation in diabetics to deliver insulin and microdialysis of the brain, a technique to separate and quantify neurotransmitters, hormones, and other biomolecules from fluid in the brain.
