Delivering therapeutic compounds to the ear, though, is no small task. Any drug-delivery system for the ear will require extremely high-precision engineering to navigate the intricate internal geometry of the cochlea. This structure contains a coiled, snail-like tube with a membrane that's covered with sensory elements and stretched across the middle of the tube. The membrane moves in response to sound, and hair cells sense the shearing forces of that motion. Fluid, called perilymph, bathes many of the functionally important elements of the cochlea, including the hair cells.
Despite the cochlea's peculiar and complex environment, the system we've built is quite simple. Our approach is to drill a single inlet hole in the scala tympani, one of the perilymph-filled cavities of the cochlea, and insert a small tube. A highly efficient, electronically controlled pump about the size of a pencil eraser will push the drug out of its reservoir through a network of valves and channels. The drug will travel through the tube, and the pump will help mix the drug with the inner ear fluid. Sensors in the device will detect the fluid flow and transmit that information to an external receiver, which will monitor the performance of the implant.
Photo: Charles Stark Draper Laboratory
Fluid Circuit: A piston compresses a chamber [left] to pump a drug reservoir [right], in this 2.5- by 1.3-centimeter element.
Click on image for larger view
The device's defining feature is its fluid circuit. Just about every introductory electrical engineering course uses the analogy of water flowing through a pipe to explain the basics of circuit design. We've taken the reverse approach, using electrical circuit elements to model the fluid-dynamic behavior of the drug-delivery system and the ear. Critical parts of our model include the resistance to flow both in the delivery device and in the cochlea, the compliance (or stretchiness) of the device and the cochlear membranes, and the driving force that the micropump must deliver to the flow.
If a tube or vessel has some elasticity, energy can be stored in the expansion and contraction of the vessel's walls, giving it a storage function comparable to electrical capacitance. So we model compliance using a capacitor. Modeling the resistance to flow in a pipe or tube is very straightforward: We use an electrical resistor analogue. The flow rate of a fluid in a pipe is analogous to the flow of current. The driving force for fluid flow—the micropump—acts like a voltage source, or power supply. The micropump generates a pressure difference between the drug reservoir and the inner ear by working against the fluidic resistance and using the storage capability of the tube's elasticity to drive the drug into the cochlea. In our model, the resistance and capacitance of the overall system includes values for inner ear structures, which are fixed, and values for our device, which can be tuned.
All of this is important because the cochlear structures in the inner ear are extremely sensitive to forces and flows. We need to provide just enough flow to deliver sufficient quantities of a drug far enough down the spiral tube. Too much flow could damage the ear, and too little would have no therapeutic effect. The resistances and capacitances within the device determine how much flow is generated by the pump and how quickly the drug is delivered to the cochlea. In other words, we can choose a particular diameter and length of tube to achieve a specific resistance and a particular elasticity to impart a specific capacitance. To tailor the timing and magnitude of doses, we can vary the intensity of the flow and the frequency of the pumping by programming a microcontroller in the device.
When we started building our device, we initially worked with silicone rubber materials that are prevalent in microfluidics, namely Silastic tubing and PDMS (for polydimethylsiloxane) components. These materials are transparent, inexpensive, and simple to fabricate, and they are generally suitable for contact with biological fluids and tissues. They also stretch nicely and therefore are excellent capacitor structures for the device. But we soon discovered a problem: The materials are permeable to air and liquid, and tiny air bubbles, barely visible to the eye, were forming inside the narrow tube that carries fluid into the cochlea. The tube is narrower than a human hair, so even a very small bubble can completely stop up the system. The air bubbles ended up acting as capacitors in our circuit, and they became an uncontrolled and unstable element in the design—sort of like having a frayed wire in intermittent contact in a circuit.
To avoid the bubbles, we switched to a less familiar material, polyimide, for most of our polymer components. It's much less permeable to air and water, and we coated the remaining permeable materials with impermeable surface layers. Of course, there was a trade-off. Most microfluidics research is done with PDMS, and engineers typically mold and cast PDMS by micromachining a silicon wafer, pouring the liquid polymer into it, and peeling out a replica molding. But micromolding polyimide is impractical, so we now use laser machining to build our micropump.
With the new materials in place, we immediately faced another challenge. The total volume of perilymph in the human cochlea is only about one-fifth of a milliliter, and so very small changes in fluid volume or pressure can damage the hair cells and other delicate structures. To avoid causing any damage, we implemented a "push-pull" system in which the drug is infused into the perilymph and then an equivalent volume of fluid is withdrawn from the cochlea, thereby maintaining a constant volume. To give the drug a chance to mix with the perilymph, we use a low-resistance, low-capacitance component to release the drug and a high-resistance, high-capacitance element to extract the fluid. That translates into a relatively rapid drug infusion pulse and a much slower and gentler withdrawal pulse. The dosage can be programmed to be constant over time, but more complex dosing profiles and combinations of multiple drugs are also possible.
The push-pull system has an added advantage that has nothing to do with the cochlea's twisted passages but everything to do with why implantable medical devices often fail. Anything that gets inserted into the body undergoes a process known as biofouling, which occurs when a foreign object triggers an inflammatory response from the body. Our concern was that fouling could potentially slow or stop the pumping action. But our system isn't static (unlike most implants), and we believe that minimal fouling will occur, because the pushing and pulling would break up any cellular or protein build-up before it becomes permanent.