Kenneth J. Dormer

Human middle ear transfer function measured by double laser interferometry system.

Hypothesis: Simultaneous measurements of vibrations on the stapes footplate, incudostapedial (IS) joint, and tympanic membrane (TM) can be made in both normal and drained cochleae, and the stapes displacement transfer function (S-DTF) and TM displacement transfer function (TM-DTF) are derived. Background: A single laser Doppler interferometer previously has been used for measuring movement of the stapes or TM in temporal bones. However, there may be a limitation to optimally describing acoustic–mechanical transmission when the interferometer and temporal bone are moved frequently during experimental recordings. Simultaneous measurements of vibrations of the TM and stapes footplate, or TM and IS joint may reveal different acoustic–mechanical characteristics of the middle ear. Methods: Dual laser interferometers simultaneously measured vibrations of the TM, IS joint, and stapes in 10 temporal bones with both intact and drained cochleae. From these measurements, the middle ear transfer function was expressed as the S-DTF, TM-DTF, and displacement transmission ratio (DTR). Results: Simultaneous displacements of the TM, IS joint, and stapes footplate induced by sound pressure in the ear canal were recorded in both amplitude and phase. The middle ear transfer functions in terms of displacement ratio confirmed published single interferometer data but provided new information from drained cochlea. Conclusion: Stapes and TM displacement transfer functions were determined using dual interferometry, provided accurate amplitude and phase relationships from stapes footplate, IS joint, and TM, with new data from drained and normal cochlea.

Mass loading on the ossicles and middle ear function.

The middle ear as a levered vibrating system for sound transmission from the external to the inner ear is affected by changes in ossicular chain mass. Mass loading of the ossicles may impair ossicular dynamics and sound transmission to the inner ear. It is incumbent on otologic surgeons and researchers of middle ear mechanics to consider the mass loading effect on middle ear function in clinical and physiological applications. The residual hearing and frequency response can change after surgery or implantation of middle ear prostheses. We conducted experiments on mass loading effects on the middle ear transfer functions by using laser Doppler interferometry and a human temporal bone model. Two implant mass loading conditions were tested on 17 fresh or fresh-frozen temporal bones and compared with the unloaded condition for the frequencies 250 to 8,000 Hz. The results show that the linearity of the middle ear function did not change, although displacement of the stapes footplate decreased after the increased masses were placed on the incudostapedial joint. The greater the mass of the implant, the less displacement was measured at the stapes footplate. We conclude that there is a quantitative limit to increased mass on the ossicular chain above which the mass will remarkably impair hearing thresholds.

An advanced computer-aided geometric modeling and fabrication method for human middle ear

This paper presents a practical and systematic method for reconstructing accurate computer and physical models of the entire human middle ear. The proposed method starts with the histological section preparation of human temporal bone. Through tracing outlines of the middle ear components on the sections, a set of discrete points is obtained and employed to construct B-spline curves that represent the exterior contours of the components using a curve-fitting technique. The surface-skinning technique is then employed to quilt the B-spline curves for smooth boundary surfaces of the middle ear components using B-spline surfaces. The solid models of the middle ear components are constructed using these surfaces and then assembled to create the entire middle ear in a computer-aided design environment. This method not only provides an effective way to visualize and measure the three-dimensional structure of the middle ear, but also provides a detailed knowledge of middle ear geometry that is required for finite element analysis or multibody dynamic analysis of the human middle ear. In addition, the geometric model constructed using the proposed method is smooth and can be fabricated in various scales using solid freeform fabrication technology. The physical model of the human middle ear is extremely effective in realizing the middle ear anatomy and enhancing discussion and collaboration among researchers and physicians.

The permeability of SPION over an artificial three-layer membrane is enhanced by external magnetic field

BackgroundSensorineural hearing loss, a subset of all clinical hearing loss, may be correctable through the use of gene therapy. We are testing a delivery system of therapeutics through a 3 cell-layer round window membrane model (RWM model) that may provide an entry of drugs or genes to the inner ear. We designed an in vitro RWM model similar to the RWM (will be referred to throughout the paper as RWM model) to determine the feasibility of using superparamagnetic iron oxide (Fe3O4) nanoparticles (SPION) for targeted delivery of therapeutics to the inner ear.The RWM model is a 3 cell-layer model with epithelial cells cultured on both sides of a small intestinal submucosal (SIS) matrix and fibroblasts seeded in between. Dextran encapsulated nanoparticle clusters 130 nm in diameter were pulled through the RWM model using permanent magnets with flux density 0.410 Tesla at the pole face. The SIS membranes were harvested at day 7 and then fixed in 4% paraformaldehyde. Transmission electron microscopy and fluorescence spectrophotometry were used to verify transepithelial transport of the SPION across the cell-culture model. Histological sections were examined for evidence of SPION toxicity, as well to generate a timeline of the position of the SPION at different times. SPION also were added to cells in culture to assess in vitro toxicity.ResultsTransepithelial electrical resistance measurements confirmed epithelial confluence, as SPION crossed a membrane consisting of three co-cultured layers of cells, under the influence of a magnetic field. Micrographs showed SPION distributed throughout the membrane model, in between cell layers, and sometimes on the surface of cells. TEM verified that the SPION were pulled through the membrane into the culture well below. Fluorescence spectrophotometry quantified the number of SPION that went through the SIS membrane. SPION showed no toxicity to cells in culture.ConclusionA three-cell layer model of the human round window membrane has been constructed. SPION have been magnetically transported through this model, allowing quantitative evaluation of prospective targeted drug or gene delivery through the RWM. Putative in vivo carrier superparamagnetic nanoparticles may be evaluated using this model.

Magnetic nanoparticles: inner ear targeted molecule delivery and middle ear implant.

Superparamagnetic iron oxide nanoparticles (SNP) composed of magnetite (Fe3O4) were studied preliminarily as vehicles for therapeutic molecule delivery to the inner ear and as a middle ear implant capable of producing biomechanically relevant forces for auditory function. Magnetite SNP were synthesized, then encapsulated in either silica or poly (D,L,-Lactide-co-glycolide) or obtained commercially with coatings of oleic acid or dextran. Permanent magnetic fields generated forces sufficient to pull them across tissue in several round window membrane models (in vitrocell culture, in vivo rat and guinea pig, and human temporal bone) or to embed them in middle ear epithelia. Biocompatibility was investigated by light and electron microscopy, cell culture kinetics, and hair cell survival in organotypic cell culture and no measurable toxicity was found. A sinusoidal magnetic field applied to guinea pigs with SNP implanted in the middle ear resulted in displacements of the middle ear comparable to 90 dB SPL.

Distribution of PLGA nanoparticles in chinchilla cochleae

Objectives To study the distribution of polylactic/glycolic acid–encapsulated iron oxide nanoparticles (PLGA-NPs) in chinchilla cochleae after application on the round window membrane (RWM). Study Design and Setting Six chinchillas (12 ears) were equally divided into controls (no treatments) and experimen-tals (PLGA-NP with or without magnetic exposure). After 40 minutes of PLGA-NP placement on the RWM, perilymph was withdrawn from the scala tympani. The RWM and cochleae were fixed with 2.5% glutaraldehyde and processed for transmission electron microscopy. Results Nanoparticles were found in cochleae with or without exposure to magnet forces appearing in the RWM, perilymph, endolymph, and multiple locations in the organ of Corti. Electron energy loss spectroscopy confirmed iron elements in nanoparticles. Conclusion The nanoparticles were distributed throughout the inner ear after application on the chinchilla RWM, with and without magnetic forces. Significance PLGA-NP applied to the RWM may have potential for sustained therapy to the inner ear.

Magnetic characterization of superparamagnetic nanoparticles pulled through model membranes

BackgroundTo quantitatively compare in-vitro and in vivo membrane transport studies of targeted delivery, one needs characterization of the magnetically-induced mobility of superparamagnetic iron oxide nanoparticles (SPION). Flux densities, gradients, and nanoparticle properties were measured in order to quantify the magnetic force on the SPION in both an artificial cochlear round window membrane (RWM) model and the guinea pig RWM.MethodsThree-dimensional maps were created for flux density and magnetic gradient produced by a 24-well casing of 4.1 kilo-Gauss neodymium-iron-boron (NdFeB) disc magnets. The casing was used to pull SPION through a three-layer cell culture RWM model. Similar maps were created for a 4 inch (10.16 cm) cube 48 MGOe NdFeB magnet used to pull polymeric-nanoparticles through the RWM of anesthetized guinea pigs. Other parameters needed to compute magnetic force were nanoparticle and polymer properties, including average radius, density, magnetic susceptibility, and volume fraction of magnetite.ResultsA minimum force of 5.04 × 10-16 N was determined to adequately pull nanoparticles through the in-vitro model. For the guinea pig RWM, the magnetic force on the polymeric nanoparticles was 9.69 × 10-20 N. Electron microscopy confirmed the movement of the particles through both RWM models.ConclusionAs prospective carriers of therapeutic substances, polymers containing superparamagnetic iron oxide nanoparticles were succesfully pulled through the live RWM. The force required to achieve in vivo transport was significantly lower than that required to pull nanoparticles through the in-vitro RWM model. Indeed very little force was required to accomplish measurable delivery of polymeric-SPION composite nanoparticles across the RWM, suggesting that therapeutic delivery to the inner ear by SPION is feasible.

A middle ear implantable hearing device for controlled amplification of sound in the human: A preliminary report

Millions of people in the United States suffer from hearing impairment that is not benefited or poorly benefited by surgery or conventional hearing aids. Recently, we introduced an implantable Temporal Bone Stimulator (TBS) designed for those patients having a hearing loss due to external canal conditions; such as, external canal atresia or disease, inoperable ossicular problems, atelectasis or eustachian tube malfunction, and chronic open‐cavity mastoid disease. This device requires relatively good cochlear function. However, the electromagnetic application of this device has led to the development of a new device we call the Implantable Hearing Device (IHD). This device stimulates, by an electromagnetic field, an independent electromagnetic sensitive prosthesis attached to the ossicular chain. This direct energy transfer to the ossicular chain provides a high degree of sound amplification and fidelity, thus providing benefit for those with various degrees of sensorineural hearing impairment.

Autonomic Denervation With Magnetic Nanoparticles

Background— Prior studies indicated that ablation of the 4 major atrial ganglionated plexi (GP) suppressed atrial fibrillation. Methods and Results— Superparamagnetic nanoparticles (MNPs) made of Fe3O4 (core), thermoresponsive polymeric hydrogel (shell), and neurotoxic agent (N-isopropylacrylamide monomer [NIPA-M]) were synthesized. In 23 dogs, a right thoracotomy exposed the anterior right GP (ARGP) and inferior right GP (IRGP). The sinus rate and ventricular rate slowing responses to high-frequency stimulation (20 Hz, 0.1 ms) were used as the surrogate for the ARGP and IRGP functions, respectively. In 6 dogs, MNPs carrying 0.4 mg NIPA-M were injected into the ARGP. In 4 other dogs, a cylindrical magnet (2600 G) was placed epicardially on the IRGP. MNPs carrying 0.8 mg NIPA-M were then infused into the circumflex artery supplying the IRGP. The hydrogel shell reliably contracted in vitro at temperatures ≥37°C, releasing NIPA-M. MNPs injected into the ARGP suppressed high-frequency stimulation–induced sinus rate slowing response (40±8% at baseline; 21±9% at 2 hours; P=0.006). The lowest voltage of ARGP high-frequency stimulation inducing atrial fibrillation was increased from 5.9±0.8 V (baseline) to 10.2±0.9 V (2 hours; P=0.009). Intracoronary infusion of MNPs suppressed the IRGP but not ARGP function (ventricular rate slowing: 57±8% at baseline, 20±8% at 2 hours; P=0.002; sinus rate slowing: 31±7% at baseline, 33±8% at 2 hours; P=0.604). Prussian Blue staining revealed MNP aggregates only in the IRGP, not the ARGP. Conclusions— Intravascularly administered MNPs carrying NIPA-M can be magnetically targeted to the IRGP and reduce GP activity presumably by the subsequent release of NIPA-M. This novel targeted drug delivery system can be used intravascularly for targeted autonomic denervation.

Middle Ear Implantable Hearing Device: Ongoing Animal and Human Evaluation

The first five patients have been permanently implanted with an electromagnetic middle ear implantable hearing device. Hearing tests were performed at the time of operation and at 8 weeks postoperatively with a coil held at the isthmus of the ear canal. All patients reported clear, high fidelity sound, as proven by speech discrimination scores. Improvements were seen in all frequencies, including 4,000 Hz. Improvement in pure tones as tested with an audiometer monitoring sounds amplified by a 3-V sound processor was as high as 50 dB sound pressure level. That which remains to be done is the final design of a compact, wearable sound processor with filtering and signal-processing capabilities to meet the needs of the sensorineural hearing-impaired population.