Skip to main content

Advertisement

SpringerLink
Log in

Microfabricated infuse-withdraw micropump component for an integrated inner-ear drug-delivery platform

  • Published:
Biomedical Microdevices Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14
Fig. 15
Fig. 16

Similar content being viewed by others

References

  • Eaton-Peabody Laboratories (2014). http://www.masseyeandear.org/research/otolaryngology/investigators/laboratories/eaton-peabody-laboratories/epl-engineering-resources/epl-cochlear-function-test-suite/

  • J. Andrews, A. Böhmer, L. Hoffman, The measurement and manipulation of intralabyrinthine pressure in experimental endolymphatic hydrops. Laryngoscope. 101, 661–668 (1991)

    Article  Google Scholar 

  • S.E. Barron, R.P. Bobbin, P. Guth, C. Norris, Cytochalasin D suppresses sound evoked potentials in the guinea pig cochlea. Hear Res. 31(2), 147–53 (1987)

    Article  Google Scholar 

  • L. Bianchi, Y. Raz, Methods for providing therapeutic agents to treat damaged spiral ganglion neurons. Curr. Drug Targets-CNS Neurol. Disord. 3, 195–199 (2004)

    Article  Google Scholar 

  • R.P. Bobbin, G. Ceasar, Kynurenic acid and γ-D-glutamylaminomethylsulfonic the compound action potential of the auditory acid suppress nerve. Hear Res. 25, 77–81 (1987)

    Article  Google Scholar 

  • A. Böhmer, On the pathomechanism of cochlear dysfunction in experimental perilymph fistulas. Laryngoscope. 101, 1307–1312 (1991)

    Article  Google Scholar 

  • A. Böhmer, J. Andrews, Maintenance of hydrostatic pressure gradients in the membranous labyrinth. Arch Otorhinolaryngol. 246, 65–66 (1989)

    Article  Google Scholar 

  • S.S. Chandrasekhar, R.Y. Rubinstein, Kwartler Ja, M. Gatz, P.E. Connelly, E. Huang, S. Baredes, Dexamethasone pharmacokinetics in the inner ear: Comparison of route of administration and use of facilitating agents. Otolaryngol – Head Neck Surg. 122(4), 521–528 (2000). doi:10.1067/mhn.2000.102578

    Google Scholar 

  • Z. Chen, S.G. Kujawa, M.J. McKenna, J.O. Fiering, M.J. Mescher, J.T. Borenstein, E.E.L. Swan, W.F. Sewell, Inner ear drug delivery via a reciprocating perfusion system in the guinea pig. J. Control. Rel. 110(1), 1–19 (2005). doi:10.1016/j.jconrel.2005.09.003

    Article  Google Scholar 

  • Z. Chen, A.A. Mikulec, M.J. McKenna, W.F. Sewell, S.G. Kujawa, A method for intracochlear drug delivery in the mouse. J. Neurosci. Methods. 150(1), 67–73 (2006). doi:10.1016/j.jneumeth.2005.05.017

    Article  Google Scholar 

  • G.P. Chrousos, in Adrenocorticosteroids and Adrenocortical Antagonists, ed. by B. Katzung. Adrenocorticosteroids Adrenocortical Antagon., (McGraw-Hill New York, 2007), pp. 635–652

  • K.J. Doyle, C. Bauch, R. Battista, C. Beatty, G.B. Hughes, J. Mason, J. Maw, F.L. Musiek, Intratympanic steroid treatment: a review. Otol. Neurotol. 25(6), 1034–9 (2004)

    Article  Google Scholar 

  • J. Eggermont, Tinnitus: neurobiological substrates. Drug Discov. Today. 10(19), 1283–1290 (2005)

    Article  Google Scholar 

  • T. Endo, T. Nakagawa, T. Kita, F. Iguchi, T.S. Kim, T. Tamura, K. Iwai, Y. Tabata, J. Ito, Novel strategy for treatment of inner ears using a biodegradable gel. Laryngoscope. 115(11), 2016–20 (2005). doi:10.1097/01.mlg.0000183020.32435.59

    Article  Google Scholar 

  • J. Fiering, M.J. Mescher, Swan E.E. Leary, M.E. Holmboe, Ba. Murphy, Z. Chen, M. Peppi, W.F. Sewell, M.J. McKenna, S.G. Kujawa, J.T. Borenstein, Local drug delivery with a self-contained, programmable, microfluidic system. Biomed. Microdevice. 11(3), 571–8 (2009). doi:10.1007/s10544-008-9265-5

    Article  Google Scholar 

  • A. Fridberger, J.T. van Maarseveen, E. Scarfone, M. Ulfendahl, B. Flock, A. Flock, Pressure-induced basilar membrane position shifts and the stimulus-evoked potentials in the low-frequency region of the guinea pig cochlea. Acta Physiol. Scand. 161(2), 239–52 (1997). doi:10.1046/j.1365-201X.1997.00214.x

    Article  Google Scholar 

  • J.R. García-Berrocal, R. Ramírez-Camacho, D. Lobo, A. Trinidad, J.M. Verdaguer, Adverse effects of glucocorticoid therapy for inner ear disorders. ORL. J. Otorhinolaryngol. Relat. Spec. 70(4), 271–4 (2008). doi:10.1159/000134381

    Article  Google Scholar 

  • G.S.G. Géléoc, J.R. Holt, Sound strategies for hearing restoration. Sci. 344(6184), 1241,062 (2014). doi:10.1126/science.1241062

    Article  Google Scholar 

  • A.F. Ghiz, A.N. Salt, J.E. DeMott, M.M. Henson, O.W. Henson, S.L. Gewalt, Quantitative anatomy of the round window and cochlear aqueduct in guinea pigs. Hear Res. 162(1–2), 105–12 (2001)

    Article  Google Scholar 

  • D. Greenwood, Comparing octaves, frequency ranges, and cochlear-map curvature across species. Hear Res. 94, 157–162 (1996)

    Article  Google Scholar 

  • D.S. Haynes, M. O’Malley , S. Cohen , K. Watford, R.F. Labadie, Intratympanic dexamethasone for sudden sensorineural hearing loss after failure of systemic therapy. Laryngoscope. 117(1), 3–15 (2007). doi:10.1097/01.mlg.0000245058.11866.15

    Article  Google Scholar 

  • C. Himeno, M. Komeda, M. Izumikawa, K. Takemura, M. Yagi, Y. Weiping, T. Doi, H. Kuriyama, J. Miller, T. Yamashita, Intra-cochlear administration of dexamethasone attenuates aminoglycoside ototoxicity in the guinea pig. Hear Res. 167, 61–70 (2002)

    Article  Google Scholar 

  • M.C. Holley, Keynote review: The auditory system, hearing loss and potential targets for drug development. Drug Discov. Today. 10(19), 1269–82 (2005). doi:10.1016/S1359-6446(05)03595-6

    Article  Google Scholar 

  • J. Ito, T. Endo, T. Nakagawa, T. Kita, T.S. Kim, F. Iguchi, A new method for drug application to the inner ear. ORL. J. Otorhinolaryngol. Relat. Spec. 67(5), 272–5 (2005). doi:10.1159/000089407

    Article  Google Scholar 

  • K. Iwai, T. Nakagawa, T. Endo, Cochlear Protection by Local Insulin-Like Growth Factor-1 Application Using Biodegradable Hydrogel. Laryngoscope. 116(4), 529–533 (2006)

    Article  Google Scholar 

  • M. Izumikawa, R. Minoda, K. Kawamoto, Ka. Abrashkin, D.L. Swiderski, D.F. Dolan, D.E. Brough, Y. Raphael, Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals. Nat. Med. 11(3), 271–6 (2005). doi:10.1038/nm1193

    Article  Google Scholar 

  • S.K. Juhn, Barrier Systems in the Inner Ear. Acta Otolaryngol. 105(s458), 79–83 (1988)

    Article  Google Scholar 

  • S.K. Juhn, L.P. Rybak, Labyrinthine Barriers and Cochlear Homeostasis. Acta Otolaryngol. 91(1–6), 529–534 (1981)

    Article  Google Scholar 

  • S.K. Juhn, B.A. Hunter, R.M. Odland, Blood-labyrinth barrier and fluid dynamics of the inner ear. Int. Tinnitus. J. 7(2), 72–83 (2001)

    Google Scholar 

  • E.S. Kim, E. Gustenhoven, M.J. Mescher, E.E.L. Pararas, Ka. Smith, A.J. Spencer, V. Tandon, J.T. Borenstein, J. Fiering, A microfluidic reciprocating intracochlear drug delivery system with reservoir and active dose control. Lab Chip. 14(4), 710–21 (2014). doi:10.1039/c3lc51105g

    Article  Google Scholar 

  • G. Li, Frenz Da, S. Brahmblatt, J.G. Feghali, R.J. Ruben, D. Berggren, J. Arezzo, T.R. Van De Water, Round window membrane delivery of L-methionine provides protection from cisplatin ototoxicity without compromising chemotherapeutic efficacy. Neurotoxicology. 22(2), 163–76 (2001)

    Article  Google Scholar 

  • H. Li, G. Roblin, H. Liu, S. Heller, Generation of hair cells by stepwise differentiation of embryonic stem cells. Proc. Natl. Acad. Sci. USA. 100(23), 13,495–500 (2003). doi:10.1073/pnas.2334503100

    Article  Google Scholar 

  • H. Li, C.E. Corrales, A. Edge, S. Heller, Stem cells as therapy for hearing loss. Trends Mol. Med. 10(7), 309–15 (2004). doi:10.1016/j.molmed.2004.05.008

    Article  Google Scholar 

  • T. Littman, R.P. Bobbin, M. Fallon, J.L. Puel, The quinoxalinediones DNQX, CNQX and two relateed congeners suppress hair cell-to-auditory nerve transmission. Hear Res. 40, 45–54 (1989)

    Article  Google Scholar 

  • E.D. Lynch, J. Kil, Compounds for the prevention and treatment of noise-induced hearing loss. Drug Discov. Today. 10(19), 1291–1298 (2005)

    Article  Google Scholar 

  • Y. Maeda, A. Sheffield, R. Smith, Therapeutic regulation of gene expression in the inner ear using RNA interference. 13–36. 66 (2009). doi:10.1159/000218205.The

  • Aa. McCall, E.E.L. Swan, J.T. Borenstein, W.F. Sewell, S.G. Kujawa, M.J. McKenna, Drug delivery for treatment of inner ear disease: current state of knowledge. Ear Hear. 31(2), 156–65 (2010). doi:10.1097/AUD.0b013e3181c351f2

    Article  Google Scholar 

  • M.J. Mescher, E.E.L. Swan, J. Fiering, M.E. Holmboe, W.F. Sewell, S.G. Kujawa, M.J. McKenna, J.T. Borenstein, Fabrication Methods and Performance of Low-Permeability Microfluidic Components for a Miniaturized Wearable Drug Delivery System. JMEMS. 18(3), 501–510 (2009)

    Google Scholar 

  • K. Mizutari, M. Fujioka, M. Hosoya, N. Bramhall, H.J. Okano, H. Okano, A.S.B. Edge, Notch inhibition induces cochlear hair cell regeneration and recovery of hearing after acoustic trauma. Neuron. 77(1), 58–69 (2013). doi:10.1016/j.neuron.2012.10.032

    Article  Google Scholar 

  • K. Murai, R. Tyler, L. Harker, J. Stouffer, Review of phramacologic treatment of tinnitus. Am. J. Otol. 13(5), 454–464 (1992)

    Google Scholar 

  • F. Noushi, R. T. Richardson, J. Hardman, G. Clark, S. O’Leary, Delivery of neurotrophin-3 to the cochlea using alginate beads. Otol. Neurotol. 26(3), 528–33 (2005)

    Article  Google Scholar 

  • K. Ohyama, A.N. Salt, R. Thalmann, Volume flow rate of perilymph in the guinea-pig cochlea. Hear Res. 35(2–3), 119–29 (1988)

    Article  Google Scholar 

  • E. Pararas, Z. Chen, J. Fiering, Kinetics of reciprocating drug delivery to the inner ear. J. Control. Release. 152(2), 270–277 (2011). doi:10.1016/j.jconrel.2011.02.021.Kinetics

    Article  Google Scholar 

  • T.N. Parks, The AMPA receptors of auditory neurons. Hear Res. 147(1-2), 77–91 (2000)

    Article  Google Scholar 

  • M. Praetorius, K. Baker, D.E. Brough, P. Plinkert, H. Staecker, Pharmacodynamics of adenovector distribution within the inner ear tissues of the mouse. Hear Res. 227(1–2), 53–8 (2007). doi:10.1016/j.heares.2006.07.002

    Article  Google Scholar 

  • R.T. Richardson, A. Wise, S. O’Leary, J. Hardman, D. Casley, G. Clark, Tracing neurotrophin-3 diffusion and uptake in the guinea pig cochlea. Hear Res. 198(1-2), 25–35 (2004). doi:10.1016/j.heares.2004.02.012

    Article  Google Scholar 

  • R.T. Richardson, F. Noushi, S. O’Leary, Inner ear therapy for neural preservation. Audiol. Neurootol. 11(6), 343–56 (2006). doi:10.1159/000095896

    Article  Google Scholar 

  • R.T. Richardson, A.K. Wise, B.C. Thompson, B.O. Flynn, P.J. Atkinson, N.J. Fretwell, J.B. Fallon, G.G. Wallace, R.K. Shepherd, G.M. Clark, S.J. O’Leary, Polypyrrole-coated electrodes for the delivery of charge and neurotrophins to cochlear neurons. Biomaterials. 30(13), 2614–24 (2009). doi:10.1016/j.biomaterials.2009.01.015

    Article  Google Scholar 

  • L. Rybak, C. Whitworth, Ototoxicity: therapeutic opportunities. Drug Discov. Today. 10(19), 1313–1321 (2005)

    Article  Google Scholar 

  • A. Salt, Y. Ma, Quantification of solute entry into cochlear perilymph through the round window membrane. Hear Res. 154, 88–97 (2001)

    Article  Google Scholar 

  • A.N. Salt, S.K.R. Plontke, Local inner-ear drug delivery and pharmacokinetics. Drug Discov. Today. 10 (19), 1299–306 (2005). doi:10.1016/S1359-6446(05)03574-9

    Article  Google Scholar 

  • W. Sewell, in Neurotransmitters and synaptic transmission, ed. by P. Dallos, A.N. Popper, R.R. Fay. Cochlea Springer Handb. Audit. Res. Vol. 8, chap 9 (Springer, New York, New York, NY, 1996), pp. 503–533

    Google Scholar 

  • W.F. Sewell, J.T. Borenstein, Z. Chen, J. Fiering, O. Handzel, M. Holmboe, E.S. Kim, S.G. Kujawa, M.J. McKenna, M.M. Mescher, B. Murphy, E.E.L. Swan, M. Peppi, S. Tao, Development of a microfluidics-based intracochlear drug delivery device. Audiol. Neurootol. 14(6), 411–22 (2009). doi:10.1159/000241898

    Article  Google Scholar 

  • Y. Shinomori, D. Spack, Volumetric and dimensional analysis of the guinea pig inner ear. Ann. Otol. Rhinol. Laryngol. 110(1), 91–98 (2001)

    Article  Google Scholar 

  • A. Shulman, B. Goldstein, Intratympanic drug therapy with steroids for tinnitus control: a preliminary report. Int. Tinnitus. J. 6(1), 10–20 (2000)

    Google Scholar 

  • E.E.L. Swan, M.J. Mescher, W.F. Sewell, S.L. Tao, J.T. Borenstein, Inner ear drug delivery for auditory applications. Adv. Drug Deliv. Rev. 60(15), 1583–99 (2008). doi:10.1016/j.addr.2008.08.001

    Article  Google Scholar 

  • E.O. Thalen, H.P. Wit, J.M. Segenhout, F.W. Albers, Dynamics of inner ear pressure change caused by intracranial pressure manipulation in the guinea pig. Acta Otolaryngol. 121(4), 470–6 (2001)

    Article  Google Scholar 

  • M. Thorne, A.N. Salt, J.E. DeMott, M.M. Henson, O.W. Henson, S.L. Gewalt, Cochlear fluid space dimensions for six species derived from reconstructions of three-dimensional magnetic resonance images. Laryngoscope. 109(10), 1661–8 (1999). doi:10.1097/00005537-199910000-00021

    Article  Google Scholar 

  • M.M. Vio, R.H. Holme, Hearing loss and tinnitus: 250 million people and a US$10 billion potential market. Drug Discov. Today. 10(00), 1263–1265 (2005)

    Article  Google Scholar 

  • W.R. Wilson, F.M. Byl, N. Laird, The Efficacy of Steroids in the Treatment of Idiopathic Sudden Hearing Loss: A Double-blind Clinical Study. Arch Otolaryngol - Head Neck Surg. 106(12), 772–776 (1980). doi:10.1001/archotol.1980.00790360050013

    Article  Google Scholar 

  • M. Yoshida, L.D. Lowry, Hydrostatic pressure measurement of endolymph and perilymph in the guinea pig cochlea. Am. J. Otolaryngol. 5(3), 159–65 (1984)

    Article  Google Scholar 

Download references

Acknowledgements

The project described was supported by Award Number R01DC006848 from the National Institute on Deafness and Other Communication Disorders. The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institute on Deafness and other Communication Disorders or the National Institutes of Health. We would also like to thank Transon Nguyen for his assistance with laser machining.

Author information

Authors and Affiliations

  1. Charles Stark Draper Laboratory, Cambridge, MA, 02139, England

    Vishal Tandon, Abigail J. Spencer, Ernest S. Kim, Erin E. L. Pararas, Mark J. Mescher, Jason Fiering & Jeffrey T. Borenstein

  2. Department of Otology and Laryngology Massachusetts Eye and Ear Infirmary and Harvard Medical School Boston, Boston, MA, 02114, USA

    Vishal Tandon, Woo Seok Kang, Michael J. McKenna, Sharon G. Kujawa & William F. Sewell

Authors
  1. Vishal Tandon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Woo Seok Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Abigail J. Spencer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ernest S. Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Erin E. L. Pararas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael J. McKenna
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sharon G. Kujawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mark J. Mescher
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jason Fiering
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. William F. Sewell
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jeffrey T. Borenstein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeffrey T. Borenstein.

Additional information

Vishal Tandon and Woo Seok Kang contributed equally to this manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tandon, V., Kang, W., Spencer, A.J. et al. Microfabricated infuse-withdraw micropump component for an integrated inner-ear drug-delivery platform. Biomed Microdevices 17, 37 (2015). https://doi.org/10.1007/s10544-014-9923-8

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s10544-014-9923-8

Keywords

Search

Navigation