A microfluidic reciprocating intracochlear drug delivery system with reservoir and active dose control

Abstract

Reciprocating microfluidic drug delivery, as compared to steady or pulsed infusion, has unique features which may be advantageous in many therapeutic applications. We have previously described a device, designed for wearable use in small animal models, which periodically infuses then withdraws a sub-microliter volume of drug solution to and from the endogenous fluid of the inner ear. This delivery approach results in zero net volume of liquid transfer while enabling mass transport of compounds to the cochlea by means of diffusion and mixing. We report here on an advanced wearable delivery system aimed at further miniaturization and complex dose protocols. Enhancements to the system include the incorporation of a planar micropump to generate reciprocating flow and a novel drug reservoir which maintains zero net volume delivery and permits programmable modulation of the drug concentration in the infused bolus. The reciprocating pump is fabricated from laminated polymer films and employs a miniature electromagnetic actuator to meet the size and weight requirements of a head-mounted in vivo 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 in vitro 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 of dose modulation. Acute in vivo 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.

Microfabricated reciprocating micropump for intracochlear drug delivery with integrated drug/fluid storage and electronically controlled dosing

“…DNQX, a glutamate receptor antagonist that suppresses CAPs without affecting the DPOAEs, 34–36 has been used as a physiological indicator because frequency-dependent changes in CAP amplitudes and thresholds in response to DNQX delivery over time can be used to infer the distribution of drug in the cochlea. 18,24,26,27 …”

“…As we have done in the past, 18,24,26,27 we used DNQX in this study as a test drug because it is a well-known glutamate receptor antagonist that reversibly disrupts hair cell to auditory nerve synaptic transmission when perfused/infused into guinea pig cochlae. 34–36 Our results (Figures 13 and 14) are consistent with previous reports, as infusion of DNQX resulted in suppression of CAP amplitudes and elevation of CAP thresholds, with minimal changes to DPOAEs.…”

“…General commercial micropumps, such as the Bartels Mikrotechnik MP6, can be assembled with other fluidic components into a functional delivery system. 24 However, as the number of components and fluidic connections between them increases, such systems become less robust. Delivery of multiple agents would require at least one pump per drug, so systems assembled using commercial pumps can become too large.…”

“…We designed, fabricated, and characterized a reciprocating micropump that incorporates all of the essential microfluidic elements into a single, integrated structure (Figure 1). Like in our previous systems, 24–26 the pump is designed to be used in a head-mounted structure for long-term drug delivery experiments in guinea pig animal models with the ultimate goal of making it implantable in the human mastoid cavity. The micropump was fabricated by laminating several machined polymer layers together to form 3-D microfluidic structures, and then mounting miniature electromagnetic actuators to the fluidics to control valve and pumping action.…”

Tissue response evaluation of the mucosa of the tympanic cavity of guinea pigs, when receiving biodegradable implant

“…Nowadays, there is an increasing interest in the treatment of human inner ear disorders by local drug delivery to the inner ear for the dual purposes of increasing efficacy and decreasing side effects [2][3][4][5] .…”