Reciprocating microfluidic medication delivery as compared to steady or pulsed infusion

Reciprocating microfluidic medication delivery as compared to steady or pulsed infusion has unique features which may be advantageous in many therapeutic applications. flow and a novel drug reservoir which maintains zero net volume delivery and permits programmable modulation of the drug concentration PSI in the infused bolus. The reciprocating pump is fabricated from laminated polymer films and employs a miniature electromagnetic actuator to meet the size and PSI weight requirements of a head-mounted guinea pig testing system. The reservoir comprises a long microchannel in series with a micropump connected in parallel with the reciprocating flow network. We characterized the response and repeatability of the planar pump and compared the results with a lumped element simulation. We also characterized the performance of the reservoir including repeatability of dosing and range MGC14452 of dose modulation. Acute experiments were performed in which the reciprocating pump was used to deliver a test compound to the cochlea of anesthetized guinea pigs to evaluate short-term safety and efficacy of the system. These advances are key steps toward realization of an implantable device for long-term therapeutic applications in humans. PSI Introduction Recent advances in molecular biology have led to new discoveries and new therapeutic possibilities for the treatment of a wide range of diseases including those of the inner ear1-5. Major clinical targets include sensorineural and noise-induced hearing loss ototoxicity protection balance disorders and tinnitus. A hurdle to effective deployment of therapeutic compounds is delivery to target organs that may be relatively inaccessible through conventional routes6 7 Therefore there is an urgent clinical need for implantable drug delivery devices capable of local programmable delivery to such organs in a safe and efficacious manner. For the inner ear systemic drug delivery generally requires high drug concentrations with the consequence that compounds may reach unintended targets. This problem is exacerbated by the presence of the blood-cochlear barrier which effectively blocks most drugs that are administered through oral or intravascular routes6 7 Even when systemic delivery may be efficacious severe side effects may result such as with the use of corticosteroids for autoimmune inner ear disease8. These are challenges for both human clinical applications and for researchers aiming to use pre-clinical models to discover new compounds to treat inner ear diseases. A safe and effective delivery system that could be worn or implanted for extended periods would succinctly address these needs. Currently the most common approach to local delivery to the inner ear is placement of drug in a gel format in the middle ear at the round window membrane intratympanic injection with reliance on passive transport through the membrane into the cochlea9-15. The main drawback to this approach is that transport is not controllable and the resulting delivery kinetics can be unpredictable. Other researchers have investigated the use of injected nanoparticles gene delivery cell-based therapies and related approaches16-29; however all of these avenues ultimately require a reliable method for drug introduction into the cochlea. A preferred approach for delivery from a pharmacological perspective is direct infusion of drug PSI where the volume and concentration of drug infused into the cochlea is known and an understanding of the fluid dynamics and pharmokinetics can enable predictable delivery. Direct infusion to the cochlea is complicated by the size and location of the cochlea: the cross-sectional area of the human scala tympani is at its largest a few millimeters and access requires penetration through the round window membrane or performing a cochleostomy by drilling through the petrous bone. Further the hair cells inside the organ of Corti are very delicate and can be damaged by fluidic and mechanical forces. The volume of the scala tympani is approximately 30 μl30; rapid injection of fluid into this volume can increase pressure which may cause permanent damage. In pre-clinical studies direct infusion.