Validation of the acoustic change complex (ACC) prediction model to predict speech perception in noise in adult patients with hearing loss: a study protocol.

BACKGROUND: Speech perception tests are essential to measure the functional use of hearing and to determine the effectiveness of hearing aids and implantable auditory devices. However, these language-based tests require active participation and are influenced by linguistic and neurocognitive skills limiting their use in patients with insufficient language proficiency, cognitive impairment, or in children. We recently developed a non-attentive and objective speech perception prediction model: the Acoustic Change Complex (ACC) prediction model. The ACC prediction model uses electroencephalography to measure alterations in cortical auditory activity caused by frequency changes. The aim is to validate this model in a large-scale external validation study in adult patients with varying degrees of sensorineural hearing loss (SNHL) to confirm the high predictive value of the ACC model and to assess its test-retest reliability. METHODS: A total of 80 participants, aged 18-65 years, will be enrolled in the study. The categories of severity of hearing loss will be used as a blocking factor to establish an equal distribution of patients with various degrees of sensorineural hearing loss. During the first visit, pure tone audiometry, speech in noise tests, a phoneme discrimination test, and the first ACC measurement will be performed. During the second visit (after 1-4 weeks), the same ACC measurement will be performed to assess the test-retest reliability. The acoustic change stimuli for ACC measurements consist of a reference tone with a base frequency of 1000, 2000, or 4000 Hz with a duration of 3000 ms, gliding to a 300-ms target tone with a frequency that is 12% higher than the base frequency. The primary outcome measures are (1) the level of agreement between the predicted speech reception threshold (SRT) and the behavioral SRT, and (2) the level of agreement between the SRT calculated by the first ACC measurement and the SRT of the second ACC measurement. Level of agreement will be assessed with Bland-Altman plots. DISCUSSION: Previous studies by our group have shown the high predictive value of the ACC model. The successful validation of this model as an effective and reliable biomarker of speech perception will directly benefit the general population, as it will increase the accuracy of hearing evaluations and improve access to adequate hearing rehabilitation.

Evaluating cochlear insertion trauma and hearing preservation after cochlear implantation (CIPRES): a study protocol for a randomized single-blind controlled trial.

BACKGROUND: In order to preserve residual hearing in patients with sensorineural hearing loss (SNHL) who receive a cochlear implant (CI), insertion trauma to the delicate structures of the cochlea needs to be minimized. The surgical approach comprises the conventional mastoidectomy-posterior tympanotomy (MPT) to arrive at the middle ear, followed by either a cochleostomy (CO) or the round window (RW) approach. Both techniques have their benefits and disadvantages. Another important aspect in structure preservation is the design of the electrode array. Two different designs are used: a "straight" lateral wall lying electrode array (LW) or a "pre-curved" perimodiolar lying electrode array (PM). Interestingly, until now, the best surgical approach and design of the implant is uncertain. Our hypothesis is that there is a difference in hearing preservation outcomes between the four possible treatment options. METHODS: We designed a monocenter, multi-arm, randomized controlled trial to compare insertion trauma between four groups of patients, with each group having a unique combination of an electrode array type (LW or PM) and surgical approach (RW or CO). In total, 48 patients will be randomized into one of these four intervention groups. Our primary objective is the comparison of postoperative hearing preservation between these four groups. Secondly, we aim to assess structure preservation (i.e., scalar translocation, with basilar membrane disruption or tip fold-over of array) for each group. Thirdly, we will compare objective outcomes of hearing and structure preservation by way of electrocochleography (ECochG). DISCUSSION: Cochlear implantation by way of a cochleostomy or round window approach, using different electrode array types, is the standard medical care for patients with severe to profound bilateral sensorineural hearing loss, as it is a relatively simple and low-risk procedure that greatly benefits patients. However, loss of residual hearing remains a problem. This trial is the first randomized controlled trial that evaluates the effect of cochlear insertion trauma of several CI treatment options on hearing preservation. TRIAL REGISTRATION: Netherlands Trial Register (NTR) NL8586 . Registered on 4 May 2020. Retrospectively registered; 3/48 participants were included before registration.

Mechanical characterization of anisotropic planar biological soft tissues using finite indentation: experimental feasibility.

Heart valve tissue engineering offers a promising alternative for current treatment and replacement strategies, e.g., synthetic or bioprosthetic heart valves. In vitro mechanical conditioning is an important tool for engineering strong, implantable heart valves. Detailed knowledge of the mechanical properties of the native tissue as well as the developing tissue construct is vital for a better understanding and control of the remodeling processes induced by mechanical conditioning. The nonlinear, anisotropic and inhomogeneous mechanical behavior of heart valve tissue necessitates a mechanical characterization method that is capable of dealing with these complexities. In a recent computational study we showed that one single indentation test, combining force and deformation gradient data, provides sufficient information for local characterization of nonlinear soft anisotropic tissue properties. In the current study this approach is validated in two steps. First, indentation tests with varying indenter sizes are performed on linear elastic PDMS rubbers and compared to tensile tests on the same specimen. For the second step, tissue constructs are engineered using uniaxial or equibiaxial static constrained culture conditions. Digital image correlation (DIC) is used to quantify the anisotropy in the tissue constructs. For both validation steps, material parameters are estimated by inverse fitting of a computational model to the experimental results.

Intermittent straining accelerates the development of tissue properties in engineered heart valve tissue.

Tissue-engineered heart valves lack sufficient amounts of functionally organized structures and consequently do not meet in vivo mechanical demands. To optimize tissue architecture and hence improve mechanical properties, various in vitro mechanical conditioning protocols have been proposed, of which intermittent straining is most promising in terms of tissue properties. We hypothesize that this is due to an improved collagen matrix synthesis, maturation, and organization, triggered by periodic straining of cells. To test this hypothesis, we studied the effect of intermittent versus constrained conditioning with time (2-4 weeks), using a novel model system of human heart valve tissue. Temporal variations in collagen production, cross-link density, and mechanical properties were quantified in engineered heart valve tissue, cyclically strained for 3-h periods, alternated with 3-h periods rest. In addition, an innovative method for vital collagen imaging was used to monitor collagen organization. Intermittent straining resulted in increased collagen production, cross-link densities, collagen organization, and mechanical properties at faster rates, as compared to constrained controls, leading to stronger tissues in shorter culture periods. This is of utmost importance for heart valve tissue engineering, where insufficient mechanical properties are currently the main limiting factor.

Quantification of the temporal evolution of collagen orientation in mechanically conditioned engineered cardiovascular tissues.

Load-bearing soft tissues predominantly consist of collagen and exhibit anisotropic, non-linear visco-elastic behavior, coupled to the organization of the collagen fibers. Mimicking native mechanical behavior forms a major goal in cardiovascular tissue engineering. Engineered tissues often lack properly organized collagen and consequently do not meet in vivo mechanical demands. To improve collagen architecture and mechanical properties, mechanical stimulation of the tissue during in vitro tissue growth is crucial. This study describes the evolution of collagen fiber orientation with culture time in engineered tissue constructs in response to mechanical loading. To achieve this, a novel technique for the quantification of collagen fiber orientation is used, based on 3D vital imaging using multiphoton microscopy combined with image analysis. The engineered tissue constructs consisted of cell-seeded biodegradable rectangular scaffolds, which were either constrained or intermittently strained in longitudinal direction. Collagen fiber orientation analyses revealed that mechanical loading induced collagen alignment. The alignment shifted from oblique at the surface of the construct towards parallel to the straining direction in deeper tissue layers. Most importantly, intermittent straining improved and accelerated the alignment of the collagen fibers, as compared to constraining the constructs. Both the method and the results are relevant to create and monitor load-bearing tissues with an organized anisotropic collagen network.

Effect of strain magnitude on the tissue properties of engineered cardiovascular constructs.

Mechanical loading is a powerful regulator of tissue properties in engineered cardiovascular tissues. To ultimately regulate the biochemical processes, it is essential to quantify the effect of mechanical loading on the properties of engineered cardiovascular constructs. In this study the Flexercell FX-4000T (Flexcell Int. Corp., USA) straining system was modified to simultaneously apply various strain magnitudes to individual samples during one experiment. In addition, porous polyglycolic acid (PGA) scaffolds, coated with poly-4-hydroxybutyrate (P4HB), were partially embedded in a silicone layer to allow long-term uniaxial cyclic mechanical straining of cardiovascular engineered constructs. The constructs were subjected to two different strain magnitudes and showed differences in biochemical properties, mechanical properties and organization of the microstructure compared to the unstrained constructs. The results suggest that when the tissues are exposed to prolonged mechanical stimulation, the production of collagen with a higher fraction of crosslinks is induced. However, straining with a large strain magnitude resulted in a negative effect on the mechanical properties of the tissue. In addition, dynamic straining induced a different alignment of cells and collagen in the superficial layers compared to the deeper layers of the construct. The presented model system can be used to systematically optimize culture protocols for engineered cardiovascular tissues.

High resolution imaging of collagen organisation and synthesis using a versatile collagen specific probe.

Collagen is the protein primarily responsible for the load-bearing properties of tissues and collagen architecture is one of the main determinants of the mechanical properties of tissues. Visualisation of changes in collagen three-dimensional structure is essential in order to improve our understanding of collagen fibril formation and remodelling, e.g. in tissue engineering experiments. A recently developed collagen probe, based on a natural collagen binding protein (CNA35) conjugated to a fluorescent dye, showed to be much more specific to collagen than existing fluorescent techniques currently used for collagen visualisation in live tissues. In this paper, imaging with this fluorescent CNA35 probe was compared to imaging with second harmonic generation (SHG) and the imaging of two- and three-dimensional collagen organisation was further developed. A range of samples (cell culture, blood vessels and engineered tissues) was imaged to illustrate the potential of this collagen probe. This images of collagen organisation showed improved detail compared to images generated with SHG, which is currently the most effective method for viewing three-dimensional collagen organisation in tissues. In conclusion, the fluorescent CNA35 probe allows easy access to high resolution imaging of collagen, ranging from very young fibrils to more mature collagen fibres. Furthermore, this probe enabled real-time visualisation of collagen synthesis in cell culture, which provides new opportunities to study collagen synthesis and remodelling.

Computational analyses of mechanically induced collagen fiber remodeling in the aortic heart valve.

To optimize the mechanical properties and integrity of tissue-engineered aortic heart valves, it is necessary to gain insight into the effects of mechanical stimuli on the mechanical behavior of the tissue using mathematical models. In this study, a finite-element (FE) model is presented to relate changes in collagen fiber content and orientation to the mechanical loading condition within the engineered construct. We hypothesized that collagen fibers aligned with principal strain directions and that collagen content increased with the fiber stretch. The results indicate that the computed preferred fiber directions run from commissure to commissure and show a strong resemblance to experimental data from native aortic heart valves.

Finite element model of mechanically induced collagen fiber synthesis and degradation in the aortic valve.

Tissue-engineered trileaflet aortic valves are a promising alternative to current valve replacements. However, the mechanical properties of these valves are insufficient for implantation at the aortic position. To simulate the effect of collagen remodeling on the mechanical properties of the aortic valve, a finite element model is presented. In this study collagen remodeling is assumed to be the net result of collagen synthesis and degradation. A limited number of fibers with low initial fiber volume fraction is defined, and depending on the loading condition, the fibers are either synthesized or degraded. The synthesis and degradation of collagen fibers are both assumed to be functions of individual fiber stretch and fiber volume fraction. Simulations are performed for closed aortic valve configurations and the open aortic valve configuration. The predicted fiber directions for the closed configurations are close to the fiber directions as measured in the native aortic valve. The model predicts the evolution in collagen fiber content and the effect of remodeling on the mechanical properties.