Differential effects of mass-loading the eardrum and stiffening the middle ear on wideband absorbance.

The current work investigated the effects of mass-loading the eardrum on wideband absorbance in humans. A non-invasive approach to mass-loading the eardrum was utilized in which water was placed on the eardrum via ear canal access. The mass-loaded absorbance was compared to absorbance measured for two alternative middle ear states: normal and stiffened. To stiffen the ear, subjects pressurized the middle ear through either exsufflation or insufflation concurrent with Eustachian tube opening. Mass-loading the eardrum was hypothesized to reduce high-frequency absorbance, whereas pressurizing the middle ear was hypothesized to reduce low- to mid-frequency absorbance. Discriminant linear analysis classification was performed to evaluate the utility of absorbance in differentiating between conditions. Water on the eardrum reduced absorbance over the 0.7- to 6-kHz frequency range and increased absorbance at frequencies below approximately 0.5 kHz; these changes approximated the pattern of changes reported in both hearing thresholds and stapes motion upon mass-loading the eardrum. Pressurizing the middle ear reduced the absorbance over the 0.125- to 4-kHz frequency range. Several classification models based on the absorbance in two- or three-frequency bands had accuracy exceeding 88%.

Coupled membranes: a mechanism of frequency filtering and transmission in the field cricket ear evidenced by micro-computed tomography, laser Doppler vibrometry and finite element analysis.

Many animals employ a second frequency filter beyond the initial filtering of the eardrum (or tympanal membrane). In the field cricket ear, both the filtering mechanism and the transmission path from the posterior tympanal membrane (PTM) have remained unclear. A mismatch between PTM vibrations and sensilla tuning has prompted speculations of a second filter. PTM coupling to the tracheal branches is suggested to support a transmission pathway. Here, we present three independent lines of evidence converging on the same conclusion: the existence of a series of linked membranes with distinct resonant frequencies serving both filtering and transmission functions. Micro-computed tomography (µ-CT) highlighted the 'dividing membrane (DivM)', separating the tracheal branches and connected to the PTM via the dorsal membrane of the posterior tracheal branch (DM-PTB). Thickness analysis showed the DivM to share significant thinness similarity with the PTM. Laser Doppler vibrometry indicated the first of two PTM vibrational peaks, at 6 and 14 kHz, originates not from the PTM but from the coupled DM-PTB. This result was corroborated by µ-CT-based finite element analysis. These findings clarify further the biophysical source of neuroethological pathways in what is an important model of behavioural neuroscience. Tuned microscale coupled membranes may also hold biomimetic relevance.

Semi-automatic algorithm to build finite element numerical models of the human hearing system from Micro-CT data.

Finite Element modeling has been an extended methodology to build numerical model to simulate the behavior of the hearing system. Due to the complexity of the system and the difficulties to reduce the uncertainties of the geometric data, they result in computationally expensive models, sometimes generic, representative of average geometries. It makes it difficult to validate the model with direct experimental data from the same specimen or to establish a patient-oriented modeling strategy. In the present paper, a first attempt to automatize the process of model building is made. The source information is geometrical information obtained from CT of the different elements that compose the system. Importing that data, we have designed the complete procedure to build a model including tympanic membrane, ossicular chain and cavities. The methodology includes the proper coupling of all the elements and the generation of the corresponding finite element model. The whole automatic procedure is not complete, as we need to make some human-assisted decisions; however, the model development time is reduced from 4 weeks to approximately 3 days. The goal of the modeling algorithm is to build a Finite Element Model with a limited computational cost. Several tasks as contour identification or model decimation are designed and integrated in order to follow a semi-automated process that allows generating a patient-oriented model.

Mechanical Effects of Medical Device Attachment to Human Tympanic Membrane.

PURPOSE: Several treatment methods for hearing disorders rely on attaching medical devices to the tympanic membrane. This study aims to systematically analyze the effects of the material and geometrical properties and location of the medical devices attached to the tympanic membrane on middle-ear vibrations. METHODS: A finite-element model of the human middle ear was employed to simulate the effects of attachment of medical devices. Various types of material and geometrical properties, locations, and modeling scenarios were investigated for the medical device. RESULTS: The attachment of the device magnifies the effects of anti-resonances of the middle ear. Additionally, the variations of the material properties of the device significantly alter the middle-ear resonance frequency while changes in the umbo and stapes footplate motions are negligible at frequencies above 5 kHz. Furthermore, modeling the device as a point mass cannot accurately represent the implanted middle-ear behavior. The variations of the diameter and height of the medical device have negligible effects on the middle-ear vibrations at frequencies below 200 Hz but can have considerable impacts at higher frequencies. The effects of changing the device height were negligible at frequencies above 2 kHz. We also discuss the effects of medical device attachment on the vibration patterns of the tympanic membrane as well as the impacts of the variations of the location of the device on the stapes footplate responses. CONCLUSION: The findings of our study aid the development and optimization of new therapeutic devices, attached to the tympanic membrane, to have the least adverse effects on middle-ear vibrations.

The influence of tympanic-membrane orientation on acoustic ear-canal quantities: A finite-element analysis.

Assuming plane waves, ear-canal acoustic quantities, collectively known as wideband acoustic immittance (WAI), are frequently used in research and in the clinic to assess the conductive status of the middle ear. Secondary applications include compensating for the ear-canal acoustics when delivering stimuli to the ear and measuring otoacoustic emissions. However, the ear canal is inherently non-uniform and terminated at an oblique angle by the conical-shaped tympanic membrane (TM), thus potentially confounding the ability of WAI quantities in characterizing the middle-ear status. This paper studies the isolated possible confounding effects of TM orientation and shape on characterizing the middle ear using WAI in human ears. That is, the non-uniform geometry of the ear canal is not considered except for that resulting from the TM orientation and shape. This is achieved using finite-element models of uniform ear canals terminated by both lumped-element and finite-element middle-ear models. In addition, the effects on stimulation and reverse-transmission quantities are investigated, including the physical significance of quantities seeking to approximate the sound pressure at the TM. The results show a relatively small effect of the TM orientation on WAI quantities, except for a distinct delay above 10 kHz, further affecting some stimulation and reverse-transmission quantities.

Auditory sensitivity and tympanic middle ear in a vocal and a non-vocal frog.

The tympanic middle ear is important for anuran hearing on land. However, many species have partly or entirely lost their tympanic apparatus. Previous studies have compared hearing sensitivities in species that possess and lack tympanic membranes capable of sound production and acoustic communication. However, little is known about how these hearing abilities are comparable to those of mutant species. Here, we compared the eardrum and middle ear anatomies of two sympatric sibling species from a noisy stream habitat, namely the "non-vocal" Hainan torrent frog (Amolops hainanensis) and the "vocal" little torrent frog (Amolops torrentis), the latter of which is capable of acoustic communication. Our results showed that the relative (to head size) eardrum diameter of A. hainanensis was smaller than that of A. torrentis, although the absolute size was not smaller. Unlike A. torrentis, the tympanic membrane area of A. hainanensis was not clearly differentiated from the surrounding skin. The middle ear, however, was well-developed in both species. We measured the auditory brainstem responses (ABRs) of A. hainanensis and compared the ABR thresholds and latencies to those previously obtained for A. torrentis. Our results suggested that these two species exhibited significant differences in hearing sensitivity. A. hainanensis (smaller relative eardrum, nonvocal) had higher ABR thresholds and longer initial response times than A. torrentis (larger relative eardrum, vocal) at lower frequencies. Neurophysiological responses from the brain were obtained for tone pips between 800 Hz and 7,000 Hz, with peak sensitivities found at 3,000 Hz (73 dB SPL) for A. hainanensis, and at 1,800 Hz (61 dB SPL) for A. torrentis. Our results suggest that the non-vocal A. hainanensis has lower hearing sensitivity than its vocal sister species (i.e., A. torrentis), which may be related to differences in tympanic or inner ear structure and morphology.

Effects of age and noise on tympanal displacement in the Desert Locust.

Insect cuticle is an evolutionary-malleable exoskeleton that has specialised for various functions. Insects that detect the pressure component of sound bear specialised sound-capturing tympani evolved from cuticular thinning. Whilst the outer layer of insect cuticle is composed of non-living chitin, its mechanical properties change during development and aging. Here, we measured the displacements of the tympanum of the desert Locust, Schistocerca gregaria, to understand biomechanical changes as a function of age and noise-exposure. We found that the stiffness of the tympanum decreases within 12 h of noise-exposure and increases as a function of age, independent of noise-exposure. Noise-induced changes were dynamic with an increased tympanum displacement to sound within 12 h post noise-exposure. Within 24 h, however, the tone-evoked displacement of the tympanum decreased below that of control Locusts. After 48 h, the tone-evoked displacement of the tympanum was not significantly different to Locusts not exposed to noise. Tympanal displacements reduced predictably with age and repeatably noise-exposed Locusts (every three days) did not differ from their non-noise-exposed counterparts. Changes in the biomechanics of the tympanum may explain an age-dependent decrease in auditory detection in tympanal insects.

The anatomical basis of amphibious hearing in the American alligator (Alligator mississippiensis).

The different velocities of sound (pressure waves) in air and water make auditory source localization a challenge for amphibious animals. The American alligator (Alligator mississippiensis) has an extracolumellar cartilage that abuts the deep surface of the tympanic membrane, and then expands in size beyond the caudal margin of the tympanum. This extracolumellar expansion is the insertion site for two antagonistic skeletal muscles, the tensor tympani, and the depressor tympani. These muscles function to modulate the tension in the tympanic membrane, presumably as part of the well-developed submergence reflex of Alligator. All crocodilians, including Alligator, have internally coupled ears in which paratympanic sinuses connect the contralateral middle ear cavities. The temporal performance of internally coupled ears is determined, in part, by the tension of the tympanic membrane. Switching between a "tensed" and "relaxed" tympanic membrane may allow Alligator to compensate for the increased velocity of sound underwater and, in this way, use a single auditory map for sound localization in two very different physical environments.

Applying video motion magnification to reveal spontaneous tympanic membrane displacement as an indirect measure of intracranial pressure in patients with brain pathologies.

BACKGROUND: The observation of tympanic membrane displacement (TMD) opens up the possibility of indirect intracranial pressure (ICP) estimation. In this study, we applied a phase-based video motion magnification (VMM) algorithm to reveal spontaneous pulse TMD waveforms (spTMD) and compare them with invasively measured ICP in patients with intracranial pathologies. METHODS: Nine adults (six traumatic brain injury and three aneurysmal subarachnoid haemorrhage; median age 44 (29-53) years admitted to the intensive care unit of Wroclaw Medical University between October 2021 and October 2022 with implanted ICP sensors were included in this retrospective study. Video recordings of the tympanic membrane were performed using a portable otoscope with a video camera and analysed by a custom-written VMM algorithm. ICP was monitored using intraparenchymal sensors and arterial blood pressure (ABP) was measured in the radial arterial lines. ICP, ABP, and spTMD videos were captured simultaneously. The pulse amplitudes of ICP (Amp_ICP), ABP (Amp_ABP) and spTMD (Amp_spTMD) were estimated using fast Fourier transform within the heart rate (HR)-related frequency range. RESULTS: Amp_spTMD was significantly correlated with mean ICP (rS = 0.73; p = 0.025) and with Amp_ICP (rS = 0.88; p = 0.002). Age was not a significant moderator of this association. There were no significant relationships between Amp_spTMD and either mean ABP, HR, or Amp_ABP. CONCLUSIONS: The study suggests that Amp_spTMD increases with the increase in mean ICP and Amp_ICP. Estimation of Amp_spTMD using the VMM algorithm has the potential to allow for non-invasive detection of the risk of elevated ICP; however, further investigation in a larger group of patients is required.

Assessment of middle ear structure and function with optical coherence tomography.

BACKGROUND: Current clinical tests for middle ear (ME) injuries and related conductive hearing loss (CHL) are lengthy and costly, lacking the ability to noninvasively evaluate both structure and function in real time. Optical coherence tomography (OCT) provides both, but its application to the audiological clinic is currently limited. OBJECTIVE: Adapt and use a commercial Spectral-Domain OCT (SD-OCT) to evaluate anatomy and sound-evoked vibrations of the tympanic membrane (TM) and ossicles in the human ME. MATERIALS AND METHODS: SD-OCT was used to capture high-resolution three-dimensional (3D) ME images and measure sound-induced vibrations of the TM and ossicles in fresh human temporal bones. RESULTS: The 3D images provided thickness maps of the TM. The system was, with some software adaptations, also capable of phase-sensitive vibrometry. Measurements revealed several modes of TM vibration that became more complex with frequency. Vibrations were also measured from the incus, through the TM. This quantified ME sound transmission, which is the essential measure to assess CHL. CONCLUSION AND SIGNIFICANCE: We adapted a commercial SD-OCT to visualize the anatomy and function of the human ME. OCT has the potential to revolutionize point-of-care assessment of ME disruptions that lead to CHL which are otherwise indistinguishable via otoscopy.

Finite-Element Modelling Based on Optical Coherence Tomography and Corresponding X-ray MicroCT Data for Three Human Middle Ears.

PURPOSE: Optical coherence tomography (OCT) is an emerging imaging modality which is non-invasive, can be employed in vivo, and can record both anatomy and vibrations. The purpose here is to explore the application of finite-element (FE) modelling to OCT data. METHODS: We recorded vibrations for three human cadaver middle ears using OCT. We also have X-ray microCT images from the same ears. Three FE models were built based on geometries obtained from the microCT images. The material properties and boundary conditions of the models were obtained from previously reported studies. RESULTS: Tympanic-membrane (TM) vibration patterns were computed for the three models and compared with the patterns measured using OCT. Frequency responses were also computed for all three models for several locations in the middle ear and compared with the OCT displacements and with the literature. The three models were compared with each other in terms of geometry and function. Parameter sensitivity analyses were done and the results were compared among the models and with the literature. The simulated TM displacement patterns are qualitatively similar to the OCT results. The simulated displacements are closer to the OCT results for 500 Hz and 1 kHz but the differences are greater at 2 kHz. CONCLUSION: This study provides an initial look at the combined use of OCT measurements and FE modelling based on subject-specific anatomy. The geometries and parameters of the existing FE models could be modified for individual patients in the future to help identify abnormalities in the middle ear.

Inaccuracies of deterministic finite-element models of human middle ear revealed by stochastic modelling.

For over 40 years, finite-element models of the mechanics of the middle ear have been mostly deterministic in nature. Deterministic models do not take into account the effects of inter-individual variabilities on middle-ear parameters. We present a stochastic finite-element model of the human middle ear that uses variability in the model parameters to investigate the uncertainty in the model outputs (umbo, stapes, and tympanic-membrane displacements). We demonstrate: (1) uncertainties in the model parameters can be magnified by more than three times in the umbo and stapes footplate responses at frequencies above 2 kHz; (2) middle-ear models are biased and they distort the output distributions; and (3) with increased frequency, the highly-uncertain regions spatially spread out on the tympanic membrane surface. Our results assert that we should be mindful when using deterministic finite-element middle-ear models for critical tasks such as novel device developments and diagnosis.

Finite element analysis of conductive hearing loss caused by fixation and detachment of ligament and tendon in the middle ear.

BACKGROUND AND OBJECTIVE: The fixation of ligament and tendon of the middle ear often occurs after chronic otitis media surgery. However, there are relatively few studies on the effect of ligament and tendon on sound transmission in the human middle ear. Here, the finite element model and lumped parameter model are used to study the effect of ligament and tendon fixation and detachment on sound transmission in human ear. METHODS: In this paper, the finite element model including the external auditory canal, middle ear and simplified inner ear is used to calculate and compare the middle ear frequency response of the normal and tympanosclerosis under pure tone stimulation. In addition, the lumped parametric model is taken into account to illustrate the effect of ligament and tendon stiffness on the human ear transmission system. RESULTS: The results indicate that the motion of the tympanic membrane and stapes is reduced by ligament and tendon fixation. Although ligament and tendon detachment have a limited effect in the piston-motion direction, the stability of motion in the plane perpendicular to the piston-motion direction is significantly reduced. Most significantly, the ligament and tendon fixation cause a hearing effect of about 18 dB, which is greater in the plane perpendicular to the piston-motion direction after ligament and tendon detachment than in the piston-motion direction. CONCLUSIONS: In this study, the calculation accuracy of the lumped parameter and the finite element model is studied, and the effect of ligament and tendon on hearing loss is further explored through the finite element model with high calculation accuracy, which is helpful to understand the role of ligament and tendon in the sound transmission mechanism of the human middle ear. The study of ligament and tendon on conductive hearing loss provides a reference for clinical treatment of tympanosclerosis.

Characterization of middle ear soft tissue damping and its role in sound transmission.

Damping plays an important role in the middle ear (ME) sound transmission system. However, how to mechanically characterize the damping of ME soft tissues and the role of damping in ME sound transmission have not yet reached a consensus. In this paper, a finite element (FE) model of the partial external and ME of the human ear, considering both Rayleigh damping and viscoelastic damping for different soft tissues, is developed to quantitatively investigate the damping in soft tissues effects on the wide-frequency response of the ME sound transmission system. The model-derived results can capture the high-frequency (above 2 kHz) fluctuations and obtain the 0.9 kHz resonant frequency (RF) of the stapes velocity transfer function (SVTF) response. The results show that the damping of pars tensa (PT), stapedial annular ligament (SAL) and incudostapedial joints (ISJ) can help smooth the broadband response of the umbo and stapes footplate (SFP). It is found that, between 1 and 8 kHz, the damping of the PT increases the magnitude and phase delay of the SVTF above 2 kHz while the damping of the ISJ can avoid excessive phase delay of the SVTF, which is important in maintaining the synchronization in high-frequency vibration but has not been revealed before. Below 1 kHz, the damping of the SAL plays a more important role, and it can decrease the magnitude but increases the phase delay of the SVTF. This study has implications for a better understanding of the mechanism of ME sound transmission.

Human middle-ear muscle pulls change tympanic-membrane shape and low-frequency middle-ear transmission magnitudes and delays.

The three-bone flexible ossicular chain in mammals may allow independent alterations of middle-ear (ME) sound transmission via its two attached muscles, for both acoustic and non-acoustic stimuli. The tensor tympani (TT) muscle, which has its insertion on the malleus neck, is thought to increase tension of the tympanic membrane (TM). The stapedius (St) muscle, which has its insertion on the stapes posterior crus, is known to stiffen the stapes annular ligament. We produced ME changes in human cadaveric temporal bones by statically pulling on the TT and St muscles. The 3D static TM shape and sound-induced umbo motions from 20 Hz to 10 kHz were measured with optical coherence tomography (OCT); stapes motion was measured using laser-Doppler vibrometry (LDV). TT pulls made the TM shape more conical and moved the umbo medially, while St pulls moved the umbo laterally. In response to sound below about 1 kHz, stapes-velocity magnitudes generally decreased by about 10 dB due to TT pulls and 5 dB due to St pulls. In the 250 to 500 Hz region, the group delay calculated from stapes-velocity phase showed a decrease in transmission delay of about 150 µs by TT pulls and 60 µs by St pulls. Our interpretation of these results is that ME-muscle activity may provide a way of mechanically changing interaural time- and level-difference cues. These effects could help the brain align head-centered auditory and ocular-centered visual representations of the environment.

Numerical model characterization of the sound transmission mechanism in the tympanic membrane from a high-speed digital holographic experiment in transient regime.

A methodology for the development of a finite element numerical model of the tympanic membrane (TM) based on experiments carried out in the time domain on a cadaveric human temporal bone is presented. Using a high-speed digital holographic (HDH) system, acoustically-induced transient displacements of the TM surface are obtained. The procedure is capable to generate and validate the finite element model of the TM by numerical and experimental data correlation. Reverse engineering approach is used to identify key material parameters that define the mechanical response of the TM. Finally, modal numerical simulations of the specimen are performed. Results show the feasibility of the methodology to obtain an accurate model of a specific specimen and to help interpret its behaviour with additional numerical simulations. STATEMENT OF SIGNIFICANCE: Improving knowledge of the dynamic behavior of the tympanic membrane is key to understanding the sound transmission system in human hearing and advance in the treatment of its pathologies. Recently we acquired a new tool to carry out experiments in transient regime by means of digital laser holography, capable of providing a large amount of information in a controlled transient test. In this work, these data are used to develop a methodology that generates a numerical model of the tympanic membrane based on numerical-experimental correlations. It is important to be able to develop models that fit specific patients. In this work, additional modal simulations are also presented that, in addition to validating the results, provide more information on the specimen.

Vibration Measurements of the Gerbil Eardrum Under Quasi-static Pressure Sweeps.

Tympanometry provides an objective measurement of the status of the middle ear. During tympanometry, the ear-canal pressure is varied, while the response of the ear to sound pressure is measured. The effects of the pressure on the mechanics of the middle ear are not well understood. This study is a continuation of our previous work in which the vibration response of the gerbil eardrum was measured in vivo under quasi-static pressure steps. In this study, we delivered a continuous pressure sweep to the middle ear and measured the vibration response at four locations for six gerbils. Vibrations were recorded using a single-point laser Doppler vibrometer and glass-coated reflective beads (diameter ~ 40 µm) at the umbo and on the mid-manubrium, posterior pars tensa and anterior pars tensa.The vibration magnitudes were similar to those in the previous step-wise pressurization experiments. Most gerbils showed repeatability within less than 10 dB for consecutive cycles. As described in the previous study, as the frequency was increased at ambient pressure, the vibration magnitude on the manubrium increased slightly to a broad peak (referred to as R1) and then decreased until a small peak appeared (referred to as R2), followed by multiple peaks and troughs as the magnitude decreased further. The low-frequency vibration magnitude (at 1 kHz) decreased monotonically as the pressure became more negative except for a dip (about 500 Pa wide) that occurred between - 700 and - 1800 Pa. The lowest overall magnitude was recorded in the dip at mid-manubrium. The vibration magnitudes also decreased as the middle-ear pressure was made more positive and were larger than those at negative pressures. R1 was only visible at negative and small positive middle-ear pressures, while R2 was visible for both positive and negative pressures. R2 split into multiple branches after the middle-ear pressure became slightly positive. No magnitude dip was visible for positive middle-ear pressures.The low-frequency vibration magnitudes at negative middle-ear pressures on the pars tensa were higher than those on the manubrium. R1 was not visible for large negative middle-ear pressures on the pars tensa. R2 appeared as a multi-peak feature on the pars tensa as well, and a higher-frequency branch on the posterior pars tensa appeared as a trough on the anterior pars tensa. The magnitude dip was not present on the pars tensa. The largest overall magnitude was recorded at the R2 peak on the posterior pars tensa.The results of this study expand on the findings of the step-wise pressurization experiments and provide further insight into the evolution of the vibration response of the eardrum under quasi-static pressures.

Interfacing Perforated Eardrums with Graphene-Based Membranes for Broadband Hearing Recovery.

Eardrum perforation and associated hearing loss is a global health problem. Grafting perforated eardrum with autologous tissues in clinic can restore low-frequency hearing but often leaves poor recovery of high-frequency hearing. In this study, the potential of incorporating a thin multilayered graphene membrane (MGM) into the eardrum for broadband hearing recovery in rats is examined. The MGM shows good biocompatibility and biostability to promote the growth of eardrum cells in a regulated manner with little sign of tissue rejection and inflammatory response. After three weeks of implantation, the MGM is found to be encapsulated by a thin layer of newly grown tissue on both sides without a significant folded overgrowth that is often seen in natural healing. The perforation is well sealed, and broadband hearing recovery (1-32 kHz) is enabled and maintained for at least 2 months. Mechanical simulations show that the high elastic modulus of MGM and thin thickness of the reconstructed eardrum play a critical role in the recovery of high-frequency hearing. This work demonstrates the promise of the use of MGM as a functional graft for perforated eardrum to recover hearing in the broadband frequency region and suggests a new acoustics-related medical application for graphene-related 2D materials.

Statistical analysis of the human middle ear mechanical properties.

Many experimental data on the human middle ear (ME) mechanics and dynamics can be found in the literature. Nevertheless, discussions about the uncertainties of these data are scarce. The present study compiles experimental data on the mechanical properties of the human ME. The summary statistics of mean and standard deviation of the data were collected and the coefficients of variation were computed and pooled. Moreover, the linear correlation and distribution were assessed for the ossicles' mass. Results show that, generally, the uncertainties of the stiffness properties of the tympanic membrane, ligaments, and tendons are larger than the uncertainties of the ossicles' mass. In addition, the uncertainties of the ME response vary across frequency. The vibration measures, such as the stapes' velocity normalized by the sound pressure at the tympanic membrane, are more uncertain than ME input impedance and reflectance. It is expected that the results presented in this study will provide the basis for the development of probabilistic models of the human ME.

A transcytotic transport mechanism across the tympanic membrane.

Drug treatments for middle ear diseases are currently delivered systemically, or locally after opening the impermeable tympanic membrane (TM). We previously used bacteriophage display to discover novel peptides that are actively transported across the intact TM, with a variety of transport rates. Peptide structures were analyzed for evidence regarding the mechanism for this unexpected transport, which was then tested by the application of chemical inhibitors. Primary sequences indicated that trans-TM peptides share one of two amino acid motifs. Secondary structures revealed that linear configurations associate with higher transport rates than coiled structures. Tertiary analysis indicated that the shared sequence motifs are prominently displayed at the free ends of rapidly transported peptide phage. The shared motifs were evaluated for similarity to known motifs. The highest probability matches were for protein motifs involved in transmembrane transport and exosomes. Overall, structural findings suggest that the shared motifs represent binding sequences. They also implicate transcytosis, a polarized cell transport mechanism consisting of endocytosis, transcellular transport, and exocytosis. Inhibitor studies indicated that macropinocytosis, retrograde transport through Golgi and exocytosis participate in transport across the TM, consistent with transcytosis. This process can be harnessed to noninvasively deliver therapeutics to the middle ear.