caa a22 4500 605480419 CHVBK 20210128100415.0 cr unu---uuuuu 210128e20150401xx s 000 0 eng 10.1007/s10544-014-9923-8 doi (NATIONALLICENCE)springer-10.1007/s10544-014-9923-8 Microfabricated infuse-withdraw micropump component for an integrated inner-ear drug-delivery platform [Elektronische Daten] [Vishal Tandon, Woo Seok Kang, Abigail Spencer, Ernest Kim, Erin Pararas, Michael McKenna, Sharon Kujawa, Mark Mescher, Jason Fiering, William Sewell, Jeffrey Borenstein] One of the major challenges in treatment of auditory disorders is that many therapeutic compounds are toxic when delivered systemically. Local intracochlear delivery methods are becoming critical in emerging treatments and in drug discovery. Direct infusion via cochleostomy, in particular, is attractive from a pharmacokinetics standpoint, as there is potential for the kinetics of delivery to be well-controlled. Direct infusion is compatible with a large number of drug types, including large, complex molecules such as proteins and unstable molecules such as siRNA. In addition, hair-cell regeneration therapy will likely require long-term delivery of a timed series of agents. This presents unknown risks associated with increasing the volume of fluid within the cochlea and mechanical damage caused during delivery. There are three key requirements for an intracochlear drug delivery system: (1) a high degree of miniaturization (2) a method for pumping precise and small volumes of fluid into the cochlea in a highly controlled manner, and (3) a method for removing excess fluid from the limited cochlear fluid space. To that end, our group is developing a head-mounted microfluidics-based system for long-term intracochlear drug delivery. We utilize guinea pig animal models for development and demonstration of the device. Central to the system is an infuse-withdraw micropump component that, unlike previous micropump-based systems, has fully integrated drug and fluid storage compartments. Here we characterize the infuse-withdraw capabilities of our micropump, and show experimental results that demonstrate direct drug infusion via cochleostomy in animal models. We utilized DNQX, a glutamate receptor antagonist that suppresses CAPs, as a test drug. We monitored the frequency-dependent changes in auditory nerve CAPs during drug infusion, and observed CAP suppression consistent with the expected drug transport path based on the geometry and tonotopic organization of the cochlea. Springer Science+Business Media New York, 2015 Drug Delivery nationallicence Microfluidics nationallicence Inner Ear nationallicence Intracochlear nationallicence CAP nationallicence DPOAE nationallicence Micropump nationallicence Tandon Vishal Charles Stark Draper Laboratory, 02139, Cambridge, MA, England aut Kang Woo Seok Department of Otology and Laryngology Massachusetts Eye and Ear Infirmary and Harvard Medical School Boston, 02114, Boston, MA, USA aut Spencer Abigail Charles Stark Draper Laboratory, 02139, Cambridge, MA, England aut Kim Ernest Charles Stark Draper Laboratory, 02139, Cambridge, MA, England aut Pararas Erin Charles Stark Draper Laboratory, 02139, Cambridge, MA, England aut McKenna Michael Department of Otology and Laryngology Massachusetts Eye and Ear Infirmary and Harvard Medical School Boston, 02114, Boston, MA, USA aut Kujawa Sharon Department of Otology and Laryngology Massachusetts Eye and Ear Infirmary and Harvard Medical School Boston, 02114, Boston, MA, USA aut Mescher Mark Charles Stark Draper Laboratory, 02139, Cambridge, MA, England aut Fiering Jason Charles Stark Draper Laboratory, 02139, Cambridge, MA, England aut Sewell William Department of Otology and Laryngology Massachusetts Eye and Ear Infirmary and Harvard Medical School Boston, 02114, Boston, MA, USA aut Borenstein Jeffrey Charles Stark Draper Laboratory, 02139, Cambridge, MA, England aut Biomedical Microdevices Springer US; http://www.springer-ny.com 17/2(2015-04-01), 1-16 1387-2176 17:2<1 2015 17 10544 https://doi.org/10.1007/s10544-014-9923-8 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10544-014-9923-8 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Tandon Vishal Charles Stark Draper Laboratory, 02139, Cambridge, MA, England aut NATIONALLICENCE 700 1- Kang Woo Seok Department of Otology and Laryngology Massachusetts Eye and Ear Infirmary and Harvard Medical School Boston, 02114, Boston, MA, USA aut NATIONALLICENCE 700 1- Spencer Abigail Charles Stark Draper Laboratory, 02139, Cambridge, MA, England aut NATIONALLICENCE 700 1- Kim Ernest Charles Stark Draper Laboratory, 02139, Cambridge, MA, England aut NATIONALLICENCE 700 1- Pararas Erin Charles Stark Draper Laboratory, 02139, Cambridge, MA, England aut NATIONALLICENCE 700 1- McKenna Michael Department of Otology and Laryngology Massachusetts Eye and Ear Infirmary and Harvard Medical School Boston, 02114, Boston, MA, USA aut NATIONALLICENCE 700 1- Kujawa Sharon Department of Otology and Laryngology Massachusetts Eye and Ear Infirmary and Harvard Medical School Boston, 02114, Boston, MA, USA aut NATIONALLICENCE 700 1- Mescher Mark Charles Stark Draper Laboratory, 02139, Cambridge, MA, England aut NATIONALLICENCE 700 1- Fiering Jason Charles Stark Draper Laboratory, 02139, Cambridge, MA, England aut NATIONALLICENCE 700 1- Sewell William Department of Otology and Laryngology Massachusetts Eye and Ear Infirmary and Harvard Medical School Boston, 02114, Boston, MA, USA aut NATIONALLICENCE 700 1- Borenstein Jeffrey Charles Stark Draper Laboratory, 02139, Cambridge, MA, England aut NATIONALLICENCE 773 0- Biomedical Microdevices Springer US; http://www.springer-ny.com 17/2(2015-04-01), 1-16 1387-2176 17:2<1 2015 17 10544