Anders Fridberger

Aminoglycoside (AG) antibiotic safety is limited by ototoxicity, the mitigation of which is vital considering bacterial resistance mediated erosion of our antibiotic arsenal. Previously, we observed tectorial membrane (TM) sequestration of Ca ²⁺ . We hypothesized that the TM sequesters other cations, including the AG gentamicin. We proposed to test the effect of TM genetic ablation on ototoxicity and TM-AG sequestration. After intraperitoneal AG-furosemide, TM-lacking Tecta ^ΔENT/ΔENT mice showed limited outer hair cell loss, unlike wildtype littermates. Spectroscopy measurements of gentamicin-Texas red (GTTR) were made in isolated wildtype and Tecta ^Y1870C TMs and guinea pig cochleae following direct or intraperitoneal GTTR administration. TM-GTTR sequestration was observed in all cases, while negatively correlated with Tecta ^Y1870C zygosity. In summary, we discovered a novel TM component in the AG ototoxicity pathway. Intact TM structure is necessary for sequestration, and the TM modulates AG ototoxicity. TM-GTTR sequestration following systemic injection indicates that this phenomenon occurs during AG therapy. Single sentence summary: Ototoxic aminoglycosides collect inside the acellular tectorial membrane of the inner ear, likely due to electrostatic interactions, and the structural status of that membrane modulates the toxic effect of those aminoglycosides on sensory hair cells.

Upon acoustic stimulation of the mammalian cochlea, a travelling wave will move in a base-to-apex direction, peaking close to the resonant place of the basilar membrane. A gradient of different resonances along the basilar membrane gives rise to frequency-place coding, or tonotopicity, throughout the majority of the cochlea. Per our previous findings, the organ of Corti in the guinea pig cochlear apex does not display tonotopicity. The behavior of the basilar membrane has not been explored throughout the cochlear apex, and so hypothetically tonotopicity is conserved at the level of this structure. Outer hair cells, which influence organ of Corti and basilar membrane mechanics, provide amplification throughout the cochlea. The mechanism for this process in the region close to the helicotrema, which is important for speech and music perception, is not fully described. Here, we describe the acoustically evoked vibrations measured using optical coherence tomography (OCT) at three locations within the guinea pig cochlear apex. We note a decline in the ratio of organ of Corti and basilar membrane gain with proximity to the helicotrema and show that distinct nonlinear behaviors are associated with each location. Phase differences between the cellular portion of the organ of Corti and basilar membrane were present and remained after furosemide treatment. We report that the frequency tuning of the apical basilar membrane is inconsistent with standard models. The analysis of nonlinearity indicates that the mechanisms governing sensory transduction, while still not elucidated, change rapidly within the apical turn—findings that are important for understanding how communication-relevant sounds are encoded by the cochlea.

The fabrication of mechanically robust and reconfigurable hydrogel filaments remains a major challenge in biofabrication of perfusable architectures, dynamic tissue models, and complex 3D cell‐laden constructs. Conventional extrusion‐based bioprinting techniques generate filaments that are soft and fragile, limiting post‐processing, scalability, and functional adaptability. Rerouting of Free‐Floating Suspended Hydrogel Filaments (REFRESH) is introduced as a biofabrication strategy that integrates an aqueous two‐phase system (ATPS)‐compatible elastic extracellular matrix mimicking bioink material with a flexible printing and post‐processing approach to overcome these constraints. This method enables the formation of highly elastic hydrogel filaments cross‐linked via strain‐promoted azide‐alkyne cycloaddition (SPAAC) of bicyclo[6.1.0]non‐4‐yne‐functionalized hyaluronan, exhibiting a strain at break exceeding 100%. The printed filaments maintain mechanical integrity during manual handling and post‐processing using textile‐inspired techniques, such as knotting and braiding, into reconfigurable 3D architectures. A distinct shape memory function enables programmed mechanical actuation and recovery of deformed structures. The hydrogel system supports high cell viability across multiple cell types and enables the fabrication of multicellular constructs with spatially defined organization. By incorporating protease‐degradable cross‐linkers, REFRESH‐generated filaments function as sacrificial templates for perfusable tubular structures. This approach significantly expands the biofabrication design space, offering new possibilities for engineering vascularized tissues and complex hydrogel‐based architectures.

Soft vibrotactile devices have the potential to expand the functionality of emerging electronic skin technologies. However, those devices often lack the necessary overall performance, sensing-actuation feedback and control, and mechanical compliance for seamless integration on the skin. Here, we present soft haptic electromagnetic actuators that consist of intrinsically stretchable conductors, pressure-sensitive conductive foams, and soft magnetic composites. To minimize joule heating, high-performance stretchable composite conductors are developed based on in situ-grown silver nanoparticles formed within the silver flake framework. The conductors are laser-patterned to form soft and densely packed coils to further minimize heating. Soft pressure-sensitive conducting polymer-cellulose foams are developed and integrated to tune the resonance frequency and to provide internal resonator amplitude sensing in the resonators. The above components together with a soft magnet are assembled into soft vibrotactile devices providing high-performance actuation combined with amplitude sensing. We believe that soft haptic devices will be an essential component in future developments of multifunctional electronic skin for future human-computer and human-robotic interfaces.

The cochlea maps tones with different frequencies to distinct anatomical locations. For instance, a faint 5000-hertz tone produces brisk responses at a place approximately 8 millimeters into the 18-millimeter-long guinea pig cochlea, but little response elsewhere. This place code pervades the auditory pathways, where neurons have “best frequencies” determined by their connections to the sensory cells in the hearing organ. However, frequency selectivity in cochlear regions encoding low-frequency sounds has not been systematically studied. Here, we show that low-frequency hearing works according to a unique principle that does not involve a place code. Instead, sound-evoked responses and temporal delays are similar across the low-frequency regions of the cochlea. These findings are a break from theories considered proven for 100 years and have broad implications for understanding information processing in the brainstem and cortex and for optimizing the stimulus delivery in auditory implants.

Mammalian hearing depends on sound-evoked displacements of the stereocilia of inner hair cells (IHCs), which cause the endogenous mechanoelectrical transducer channels to conduct inward currents of cations including Ca²⁺. Due to their presumed lack of contacts with the overlaying tectorial membrane (TM), the putative stimulation mechanism for these stereocilia is by means of the viscous drag of the surrounding endolymph. However, despite numerous efforts to characterize the TM by electron microscopy and other techniques, the exact IHC stereocilia-TM relationship remains elusive. Here we show that Ca²⁺-rich filamentous structures, that we call Ca²⁺ ducts, connect the TM to the IHC stereocilia to enable mechanical stimulation by the TM while also ensuring the stereocilia access to TM Ca²⁺. Our results call for a reassessment of the stimulation mechanism for the IHC stereocilia and the TM role in hearing.

Millions of people are affected by hearing loss. Hearing loss is frequently caused by noise or aging and often associated with loss of pericytes. Pericytes populate the small vessels in the adult cochlea. However, their role in different types of hearing loss is largely unknown. Using an inducible and conditional pericyte depletion mouse model and noise-exposed mouse model, we show that loss of pericytes leads to marked changes in vascular structure, in turn leading to vascular degeneration and hearing loss. In vitro, using advanced tissue explants from pericyte fluorescence reporter models combined with exogenous donor pericytes, we show that pericytes, signaled by VEGF isoform A165 (VEGFA165), vigorously drive new vessel growth in both adult and neonatal mouse inner ear tissue. In vivo, the delivery of an adeno-associated virus serotype 1–mediated (AAV1–mediated) VEGFA165 viral vector to pericyte-depleted or noise-exposed animals prevented and regenerated lost pericytes, improved blood supply, and attenuated hearing loss. These studies provide the first clear-cut evidence that pericytes are critical for vascular regeneration, vascular stability, and hearing in adults. The restoration of vascular function in the damaged cochlea, including in noise-exposed animals, suggests that VEGFA165 gene therapy could be a new strategy for ameliorating vascular associated hearing disorders.