scholarly journals A modular microreservoir for active implantable drug delivery

2019 ◽  
Author(s):  
Farzad Forouzandeh ◽  
Xiaoxia Zhu ◽  
Nuzhet N. Ahamed ◽  
Joseph P. Walton ◽  
Robert D. Frisina ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Sacrificial Layer ◽  
Round Window ◽  
Round Window Membrane ◽  
Basal Region ◽  
Distortion Product Otoacoustic Emission ◽  
Subcutaneous Implantation ◽  
Restoring Force ◽  
Distortion Product

ABSTRACTActive implantable microscale reservoir-based drug delivery systems enabled novel and effective drug delivery concepts for both systemic and localized drug delivery applications. These systems typically consist of a drug reservoir and an active pumping mechanism for precise delivery of drugs. Here we present a stand-alone, refillable, scalable, and fully implantable microreservoir platform to be integrated with micropumps as a storing component of active implantable drug delivery microsystems. The microreservoir was fabricated with 3D-printing technology, enabling miniature, scalable, and planar structure, optimized for subcutaneous implantation especially in small animals (e.g., mouse), while being readily scalable for larger animals and human translation. Three different capacities of the microreservoir (1 μL, 10 μL, and 100 μL) were fabricated and characterized all with 3 mm thickness. The microreservoir consists of two main parts: a cavity for long-term drug storage with an outlet microtubing (250 μm OD, 125 μm ID), and a refill port for transcutaneous refills through a septum. The cavity membrane is fabricated with thin Parylene-C layers using a polyethylene glycol sacrificial layer, minimizing restoring force and hence backflow, as fluid is discharged. This feature enables integration to normally-open mechanisms and improves pumping efficiency when integrated to normally-closed pumps. The results of in vitro optimization and characterization of the cavity membrane show 95% extraction percentage of the cavity with insignificant (2%) backflow due to restoring force of the membrane. The refill port septum thickness is minimized down to 1 mm by a novel pre-compression concept, while capable of ~65000 injections with 30 Ga non-coring needles without leakage under 100 kPa (4× greater than physiological backpressure). To demonstrate integrability of the microreservoir to an active micropump, the 10 μL microreservoir was integrated to a micropump recently developed in our laboratory, making an implantable drug delivery microsystem. Two different microsystems were subcutaneously implanted in two mice, and the outlet microtubing was implanted into the round window membrane niche for infusion of a known ototoxic compound (sodium salicylate) at 50 nL/min for 20 min. Real-time shifts in distortion product otoacoustic emission thresholds and amplitudes were measured during the infusion. The in vivo results show a mean shift of 22.1 dB after 20 min for the most basal region, matching with syringe pump results. A biocompatibility experiment was performed on the microsystem for six months to assess design and fabrication suitability for chronic subcutaneous implantation and clinical translational development. The results demonstrate very favorable signs of biocompatibility for long-term implantation. Although tested here on mice for a specific inner ear application, this low-cost design and fabrication methodology is scalable for use in larger animals and human for different applications/delivery sites.

scholarly journals A Wirelessly Controlled Scalable 3D-Printed Microsystem for Drug Delivery

2021 ◽  
Vol 14 (6) ◽  
pp. 538
Author(s):  
Farzad Forouzandeh ◽  
Nuzhet N. Ahamed ◽  
Xiaoxia Zhu ◽  
Parveen Bazard ◽  
Krittika Goyal ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Printed Circuit Board ◽  
Low Cost ◽  
Round Window ◽  
Circuit Board ◽  
Round Window Membrane ◽  
Distortion Product Otoacoustic Emission ◽  
Distortion Product ◽  
3D Printed

Here we present a 3D-printed, wirelessly controlled microsystem for drug delivery, comprising a refillable microreservoir and a phase-change peristaltic micropump. The micropump structure was inkjet-printed on the back of a printed circuit board around a catheter microtubing. The enclosure of the microsystem was fabricated using stereolithography 3D printing, with an embedded microreservoir structure and integrated micropump. In one configuration, the microsystem was optimized for murine inner ear drug delivery with an overall size of 19 × 13 × 3 mm3. Benchtop results confirmed the performance of the device for reliable drug delivery. The suitability of the device for long-term subcutaneous implantation was confirmed with favorable results of implantation of a microsystem in a mouse for six months. The drug delivery was evaluated in vivo by implanting four different microsystems in four mice, while the outlet microtubing was implanted into the round window membrane niche for infusion of a known ototoxic compound (sodium salicylate) at 50 nL/min for 20 min. Real-time shifts in distortion product otoacoustic emission thresholds and amplitudes were measured during the infusion, demonstrating similar results with syringe pump infusion. Although demonstrated for one application, this low-cost design and fabrication methodology is scalable for use in larger animals and humans for different clinical applications/delivery sites.

scholarly journals The Effects of Round Window Membrane Injury and the Use of a Model Electrode Application on Hearing in Rats

2021 ◽  
pp. 014556132199018
Author(s):  
Murat Koc ◽  
Abdullah Dalgic ◽  
Mehmet Ziya Ozuer
Keyword(s):  
Hearing Loss ◽  
Cochlear Implant ◽  
Round Window ◽  
Mechanical Trauma ◽  
Round Window Membrane ◽  
Albino Rats ◽  
Topical Steroids ◽  
Distortion Product ◽  
Significant Difference ◽  
Group 3

Objective: To investigate the effects of the mechanical trauma to the round window, a model electrode inserted into the scala tympani on the cochlear reserve, and the efficacy of topical steroids in preventing hearing loss. Materials and Methods: 21 male Wistar Albino rats were equally categorized into three groups. In all groups an initial mechanical injury to round window was created. Only subsequent dexamethasone injection was administrated into the cochlea in the subjects of group 2 while a multichannel cochlear implant guide inserted into the cochlea prior to dexamethasone administration for group 3. Distortion product otoacoustic emissions (DPOAEs) were obtained prior to and immediately after the surgical injury, eventually on postoperative seventh day (d 7). Mean signal/noise ratios (S/Ns) obtained at 2000, 3000, and 4000 Hz were calculated. Data sets were compared with non-parametric statistical tests. Results: The early intraoperative mean S/Ns were significantly less than preoperative measurements for group 1 and 2; however, preoperative and postoperative d 7 average S/Ns did not differ. There was statistically significant difference between preoperative, intraoperative and postoperative d 7 average S/Ns for group 3. Conclusion: We observed that hearing was restored approximately to the preoperative levels following early postoperative repair. However, an electrode insertion into the cochlea via round window subsequent to mechanical trauma seems to cause a progressive hearing loss. Therefore, a special care must be taken to avoid the injury to the round window membrane in the course of the placement of a cochlear implant electrode and surgery for the chronic otitis media.

Paradoxical long-term enhancement of distortion product otoacoustic emission amplitude after repeated exposure to moderate level, wide band noise in awake guinea pigs

2009 ◽  
Vol 123 (10) ◽  
pp. 1090-1096 ◽  
Author(s):  
L Mei ◽  
Z-W Huang ◽  
Z-Z Tao
Keyword(s):  
Guinea Pigs ◽  
Noise Exposure ◽  
Wide Band ◽  
Otoacoustic Emission ◽  
Threshold Shift ◽  
Distortion Product Otoacoustic Emission ◽  
Distortion Product ◽  
Band Noise ◽  
Wide Band Noise

AbstractObjective:Hearing sensitivity usually diminishes with noise exposure. In the present study, we examined the effect of 93 dB(A) wide band noise on cochlear micromechanical sensitivity in awake guinea pigs.Methods:Animals were randomly assigned to groups receiving either single or repeated noise exposure. Distortion product otoacoustic emission amplitudes were recorded before, during and after noise exposure.Results:Ninety-three decibel(A) wide band noise reduced the distortion product otoacoustic emission amplitudes at all tested frequencies. The distortion product otoacoustic emission amplitudes for higher frequencies showed a permanent reduction, whereas those for lower frequencies showed a temporary reduction. Distortion product otoacoustic emission amplitudes for middle frequencies showed prolonged enhancement after repeated noise exposure.Conclusion:Our results suggest that (1) it is likely that there are intermediate stages between permanent threshold shift and temporary threshold shift, and (2) long-term enhancement of distortion product otoacoustic emission amplitudes may be an indication of tinnitus generation.

Minimally invasive drug delivery to the cochlea through application of nanoparticles to the round window membrane

Nanomedicine ◽  
2012 ◽  
Vol 7 (9) ◽  
pp. 1339-1354 ◽  
Author(s):  
Daniela Buckiová ◽  
Sanjeev Ranjan ◽  
Tracey A Newman ◽  
Alexander H Johnston ◽  
Rohit Sood ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Minimally Invasive ◽  
Round Window ◽  
Round Window Membrane

scholarly journals The Immediate and Long-Term Impact of Military Aircraft Noise on Hearing: A Cross-Sectional Comparison of Fighter Pilots and Ground Staff

2021 ◽  
Vol 18 (6) ◽  
pp. 2982
Author(s):  
Chao-Yin Kuo ◽  
Chia-Lien Hung ◽  
Hsin-Chien Chen ◽  
Cheng-Ping Shih ◽  
Rou-Huei Lu ◽  
...  
Keyword(s):  
High Frequency ◽  
Noise Exposure ◽  
Pure Tone Audiometry ◽  
Aircraft Noise ◽  
Distortion Product Otoacoustic Emission ◽  
Military Aircraft ◽  
Cross Sectional ◽  
Distortion Product ◽  
Hearing Thresholds

We examined the immediate and long-term impacts of military aircraft noise exposure on noise-induced hearing loss (NIHL) in fighter pilots and ground staff. We recruited 40 pilots, 40 ground staff, and 136 age-matched controls; all participants underwent hearing tests, including conventional pure-tone audiometry (PTA) (0.25–8.0 kHz), extended high-frequency (EHF) audiometry (9.0–18.0 kHz), and distortion-product otoacoustic emission (DPOAE) as a recent reference. A subsequent hearing test immediately after flight-mission noise exposure was requested. The results revealed higher recent hearing thresholds in pilots and ground staff than in controls. Threshold shifts at many octave band frequencies were also significantly elevated in ground staff. The grouped frequency threshold was significantly elevated in the 4–8 kHz high-frequency range. After a single flight-mission noise exposure, both ground staff and pilots showed decreased signal-to-noise ratios for DPOAE (1–8 kHz), whereas only ground staff showed significantly elevated left-ear hearing thresholds at 3, 11.2, and 12.5 kHz by conventional and EHF PTA. Fighter pilots and ground staff serve in hazardous noise-exposed environments that cause hearing damage and subsequent NIHL, but ground staff may be more vulnerable. A comprehensive hearing conservation program should be implemented to protect high-risk service members, and especially ground staff, from high-intensity noise exposure.

scholarly journals Population-based otoscopic and audiometric assessment of a birth cohort recruited for a pneumococcal vaccine trial 15–18 years earlier: a protocol

BMJ Open ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. e042363
Author(s):  
Kenny Chan ◽  
Phyllis Carosone-Link ◽  
Mary Thatcher G Bautista ◽  
Diozele Sanvictores ◽  
Kristin Uhler ◽  
...  
Keyword(s):  
Pneumococcal Vaccine ◽  
Healthcare Providers ◽  
Vaccine Trial ◽  
The Philippines ◽  
Institutional Review Board ◽  
Protective Effects ◽  
Distortion Product Otoacoustic Emission ◽  
Distortion Product ◽  
Institutional Review

IntroductionA cohort of 12 000 children in the Philippines who had enrolled in a 2000–2004 (current ages 16 to 20 years) Phase 3 11-valent pneumococcal conjugate vaccine for the prevention of radiographically confirmed pneumonia are now being asked to participate in a separate study (expected completion date September 2021) to assess the cohort’s current long-term audiometric and otologic status. This new study would allow assessments of the utility of the pneumococcal vaccine in conferring its protective effects on the long-term sequelae of otitis media (OM), if any. Lack of trained local healthcare providers in otolaryngology/audiology and testing equipment in Bohol, Philippines, necessitates the development of a distinct methodology that would lead to meaningful data analysis.Methods and analysisReliable data collection and transfer are achieved by a US otolaryngologist/audiologist team training local nurses on all procedures in a didactic and hands-on process. An assortment of portable otolaryngologic and audiologic equipment suitable for field testing has been acquired, including an operating otoscope (Welch-Allyn), a video-otoscope (JedMed), a tympanometer with distortion product otoacoustic emission measurements (Path Sentiero) and a screening audiometer (HearScreen). Data will then be uploaded to a Research Electronic Data Capture database in the USA.Tympanometric and audiologic data will be codified through separate conventional algorithms. A team of paediatric otolaryngology advanced practice providers (APPs) have been trained and validated in interpreting video otoscopy. The protocol for classification of diagnostic outcome variables based on video otoscopy and tympanometry has been developed and is being used by APPs to evaluate all otoscopy data.Ethics and disseminationThe study was approved by the Research Institute of Tropical Medicine, Alabang, Manila, Philippines, and the institutional review board and the Colorado Multiple Institutional Review Board of the University of Colorado School of Medicine, Aurora, Colorado, USA.Research results will be made available to children and their caregivers with abnormal audiologic outcomes, the funders and other researchers.Trial registration numberISRCTN 62323832; Post-results.

scholarly journals Effects of Calcitonin-Gene-Related-Peptide on Auditory Nerve Activity

2021 ◽  
Vol 9 ◽  
Author(s):  
Colleen G. Le Prell ◽  
Larry F. Hughes ◽  
David F. Dolan ◽  
Sanford C. Bledsoe
Keyword(s):  
Auditory Nerve ◽  
Outer Hair Cell ◽  
Round Window ◽  
Calcitonin Gene Related Peptide ◽  
Distortion Product Otoacoustic Emission ◽  
Nerve Activity ◽  
Distortion Product ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Brainstem Response

Calcitonin-gene-related peptide (CGRP) is a lateral olivocochlear (LOC) efferent neurotransmitter. Depression of sound-driven auditory brainstem response amplitude in CGRP-null mice suggests the potential for endogenous CGRP release to upregulate spontaneous and/or sound-driven auditory nerve (AN) activity. We chronically infused CGRP into the guinea pig cochlea and evaluated changes in AN activity as well as outer hair cell (OHC) function. The amplitude of both round window noise (a measure of ensemble spontaneous activity) and the synchronous whole-nerve response to sound (compound action potential, CAP) were enhanced. Lack of change in both onset adaptation and steady state amplitude of sound-evoked distortion product otoacoustic emission (DPOAE) responses indicated CGRP had no effect on OHCs, suggesting the origin of the observed changes was neural. Combined with results from the CGRP-null mice, these results appear to confirm that endogenous CGRP enhances auditory nerve activity when released by the LOC neurons. However, infusion of the CGRP receptor antagonist CGRP (8–37) did not reliably influence spontaneous or sound-driven AN activity, or OHC function, results that contrast with the decreased ABR amplitude measured in CGRP-null mice.

Cochlear Endoscopy with Preservation of Hearing in Guinea Pigs

1994 ◽  
Vol 111 (4) ◽  
pp. 439-445 ◽  
Author(s):  
Thomas Balkany ◽  
Annelle V. Hodges ◽  
Martin Whitehead ◽  
Faramarz Memari ◽  
Glen K. Martin
Keyword(s):  
Guinea Pig ◽  
Brain Stem ◽  
Guinea Pigs ◽  
Otoacoustic Emissions ◽  
Round Window ◽  
Distortion Product Otoacoustic Emission ◽  
Auditory Brain Stem Response ◽  
Distortion Product ◽  
Guinea Pig Cochlea ◽  
Auditory Brain Stem

Advances in fiberoptic technology have revolutionized the way many disorders are treated by otolaryngologists. We have previously described our experiences with cochlear endoscopy during cochlear Implantation. However, endoscopy of the functioning cochlea has not previously been reported. To test the hypothesis that endoscopy of the guinea pig cochlea is possible without catastrophic loss of auditory function, we subjected 20 ears of 10 Hartley-strain albino guinea pigs to limited endoscopy of the cochlea through the round window with evaluation of distortion product otoacoustic emissions and auditory brain stem responses. Insertion of the endoscope caused measurable changes in auditory brain stem response latency and amplitude. Distortion product otoacoustic emission amplitudes were reduced an average of 6 dB with greater loss close to the round window. Frequencies above 18 kHz, corresponding to the region of endoscopy, were not evaluated in this preliminary study and are suspected to have sustained more damage. Results demonstrate that endoscopy of the guinea pig cochlea is possible without major loss of the above physiologic measures in the regions tested. If endoscopy of the cochlea is to become a tool with clinical and basic science applications, refinements in techniques to avoid damage are necessary.

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