Reduced Sialylation of Airway Mucin Impairs Mucus Transport by Altering the Biophysical Properties of Mucin.

Mucus stasis is a pathologic hallmark of muco-obstructive diseases, including cystic fibrosis (CF). Mucins, the principal component of mucus, are extensively modified with hydroxyl (O)-linked glycans, which are largely terminated by sialic acid. Sialic acid is a negatively charged monosaccharide and contributes to the biochemical/biophysical properties of mucins. Reports suggest that mucin sialylation may be altered in CF; however, the consequences of reduced sialylation on mucus clearance have not been fully determined. Here, we investigated the consequences of reduced sialylation on the charge state and conformation of the most prominent airway mucin, MUC5B, and defined the functional consequences of reduced sialylation on mucociliary transport (MCT). Reduced sialylation contributed to a lower charged MUC5B form and decreased polymer expansion. The inhibition of total mucin sialylation de novo impaired MCT in primary human bronchial epithelial cells and rat airways, and specific α-2,3 sialylation blockade was sufficient to recapitulate these findings. Finally, we show that ST3 beta-galactoside alpha-2,3-sialyltransferase (ST3Gal1) expression is downregulated in CF and partially restored by correcting CFTR via Elexacaftor/Tezacaftor/Ivacaftor treatment. Overall, this study demonstrates the importance of mucin sialylation in mucus clearance and identifies decreased sialylation by ST3Gal1 as a possible therapeutic target in CF and potentially other muco-obstructive diseases.

Intravital imaging of mucus transport in asthmatic mice using microscopic optical coherence tomography.

Asthma is one of the most common chronic diseases. Mucus overproduction is consistently linked to asthma morbidity and mortality. Despite the knowledge of the importance of mucus, little data exist on how mucus is transported in asthma and the immediate effects of therapeutic intervention. We therefore used microscopic optical coherence tomography (mOCT) to study spontaneous and induced mucus transport in an interleukin-13 (IL-13)-induced asthma mouse model and examined the effects of isotonic (0.9% NaCl) and hypertonic saline (7% NaCl), which are used to induce mucus transport in cystic fibrosis. Without intervention, no bulk mucus transport was observed by mOCT and no intraluminal mucus was detectable in the intrapulmonary airways by histology. Administration of ATP-γ-S induced mucus secretion into the airway lumen, but it did not result in bulk mucus transport in the trachea. Intraluminal-secreted immobile mucus could be mobilized by administration of isotonic or hypertonic saline but hypertonic saline mobilized mucus more reliably than isotonic saline. Irrespective of saline concentration, the mucus was transported in mucus chunks. In contrast to isotonic saline solution, hypertonic saline solution alone was able to induce mucus secretion. In conclusion, mOCT is suitable to examine the effects of mucus-mobilizing therapies in vivo. Although hypertonic saline was more efficient in inducing mucus transport, it induced mucus secretion, which might explain its limited benefit in patients with asthma.

Radiation-Free Thoracic Endovascular Aneurysm Repair with Fiberoptic and Electromagnetic Guidance: A Phantom Study.

PURPOSE: To evaluate the feasibility and accuracy of a radiation-free implantation of a thoracic aortic stent graft employing fiberoptic and electromagnetic tracking in an anthropomorphic phantom. MATERIALS AND METHODS: An anthropomorphic phantom was manufactured based on computed tomography (CT) angiography data from a patient. An aortic stent graft application system was equipped with a fiber Bragg gratings and 3 electromagnetic sensors. The stent graft was navigated in the phantom by 3 interventionalists using the tracking data generated by both technologies. One implantation procedure was performed. The technical success of the procedure was evaluated using digital subtraction angiography and CT angiography (before and after the intervention). Tracking accuracy was determined at various anatomical landmarks based on separately acquired fluoroscopic images. The mean/maximum errors were measured for the stent graft application system and the tip/end of the stent graft. RESULTS: The procedure resulted in technical success with a mean error below 3 mm for the entire application system and <2 mm for the position of the tip of the stent graft. Navigation/implantation and handling of the device were rated sufficiently accurate and on par with comparable, routinely used stent graft application systems. CONCLUSIONS: The study demonstrates successful stent graft implantation during a thoracic endovascular aortic repair procedure employing advanced guidance techniques and avoiding fluoroscopic imaging. This is an essential step in facilitating the implantation of stent grafts and reducing the health risks associated with ionizing radiation during endovascular procedures.

Instrument localisation for endovascular aneurysm repair: Comparison of two methods based on tracking systems or using imaging.

BACKGROUND: In endovascular aneuysm repair (EVAR) procedures, medical instruments are currently navigated with a two-dimensional imaging based guidance requiring X-rays and contrast agent. METHODS: Novel approaches for obtaining the three-dimensional instrument positions are introduced. Firstly, a method based on fibre optical shape sensing, one electromagnetic sensor and a preoperative computed tomography (CT) scan is described. Secondly, an approach based on image processing using one 2D fluoroscopic image and a preoperative CT scan is introduced. RESULTS: For the tracking based method, average errors from 1.81 to 3.13 mm and maximum errors from 3.21 to 5.46 mm were measured. For the image-based approach, average errors from 3.07 to 6.02 mm and maximum errors from 8.05 to 15.75 mm were measured. CONCLUSION: The tracking based method is promising for usage in EVAR procedures. For the image-based approach are applications in smaller vessels more suitable, since its errors increase with the vessel diameter.

Clinical Evaluation of an Instrument-Integrated OCT-Based Distance Sensor for Robotic Vitreoretinal Surgery.

Purpose: To assess the efficacy of an instrument-integrated OCT (iiOCT)-based distance sensor during robotic vitreoretinal surgery using the Preceyes Surgical System (PSS; Preceyes B.V.). Design: Single-center interventional study. Participants: Patients requiring vitreoretinal surgery. Methods: Five patients were enrolled. Standard preoperative OCT images were obtained. After vitrectomy, a predefined set of actions was performed using the iiOCT-based sensor. Images then were processed to assess the signal-to-noise ratio (SNR) at various angles to the retina and at different distances between the instrument tip and the retinal surface. Preoperative and intraoperative OCT images were compared qualitatively and quantitatively. Main Outcomes Measures: The feasibility in performing surgical tasks using the iiOCT-based sensor during vitreoretinal surgery, the SNR when imaging the retina, differences among intraoperative and preoperative OCT images, and characteristics of intraoperative retinal movements detected with the iiOCT-based probe. Results: Surgeons were able to perform all the tasks but one. The PSS was able to maintain a fixed distance. The SNR of the iiOCT-based sensor signal was adequate to determine the distance to the retina and to control the PSS. Analysis of iiOCT-based sensor A-scans identified 3 clearly distinguishable retinal layers, including the inner retinal boundary and the interface at the retinal pigment epithelium-Bruch's membrane. Thickness values differed by less than 5% from that measured by preoperative OCT, indicating its accuracy. The Fourier analysis of iiOCT-based sensor recordings identified anteroposterior retinal movements attributed to heartbeat and respiration. Conclusions: This iiOCT-based sensor was tested successfully and promises reliable use during robot-assisted surgery. An iiOCT-based sensor is a promising step toward OCT-guided robotic retinal surgery.

Refractive Changes After Corneal Stromal Filler Injection for the Correction of Hyperopia.

PURPOSE: To evaluate a new non-ablative and adjustable procedure for laser ablative refractive corneal surgery in hyperopia using the injection of a biocompatible liquid filler material into a stromal pocket. METHODS: A total of 120 stromal pockets were created using a clinical femtosecond laser system in 96 rabbit corneoscleral discs and 24 whole globes. Pockets were cut at a depth of 120 or 250 µm below the epithelial surface. Hyaluronic acid was injected manually into the pocket. To determine the refractive changes, three-dimensional optical coherence tomography images and a specifically developed picture recognition Matlab (The Mathworks) routine were used. RESULTS: After injection, a steepening of the anterior and flattening of the posterior corneal surface was observed, which led to hyperopic correction. The two main factors determining the amount of correction were the pocket depth and the injected volume. After the pocket was homogeneously filled, an initial refractive increase was observed, followed by a linear relation between the injected volume and the refraction increase. CONCLUSIONS: This possible clinical protocol for controlled refraction correction of hyperopia suggests a potential readjustable clinical application. [J Refract Surg. 2020;36(6):406-414.].

Three-dimensional guidance including shape sensing of a stentgraft system for endovascular aneurysm repair.

PURPOSE: During endovascular aneurysm repair (EVAR) procedures, medical instruments are guided with two-dimensional (2D) fluoroscopy and conventional digital subtraction angiography. However, this requires X-ray exposure and contrast agent is used, and the depth information is missing. To overcome these drawbacks, a three-dimensional (3D) guidance approach based on tracking systems is introduced and evaluated. METHODS: A multicore fiber with fiber Bragg gratings for shape sensing and three electromagnetic (EM) sensors for locating the shape were integrated into a stentgraft system. A model for obtaining the located shape of the first 38 cm of the stentgraft system with two EM sensors is introduced and compared with a method based on three EM sensors. Both methods were evaluated with a vessel phantom containing a 3D-printed vessel made of silicone and agar-agar simulating the surrounding tissue. RESULTS: The evaluation of the guidance methods resulted in average errors from 1.35 to 2.43 mm and maximum errors from 3.04 to 6.30 mm using three EM sensors, and average errors from 1.57 to 2.64 mm and maximum errors from 2.79 to 6.27 mm using two EM sensors. Moreover, the videos made from the continuous measurements showed that a real-time guidance is possible with both approaches. CONCLUSION: The results showed that an accurate real-time guidance with two and three EM sensors is possible and that two EM sensors are already sufficient. Thus, the introduced 3D guidance method is promising to use it as navigation tool in EVAR procedures. Future work will focus on developing a method with less EM sensors and a detailed latency evaluation of the guidance method.

Intravital microscopic optical coherence tomography imaging to assess mucus-mobilizing interventions for muco-obstructive lung disease in mice.

Airway mucus obstruction is a hallmark of chronic lung diseases such as cystic fibrosis, asthma, and COPD, and the development of more effective mucus-mobilizing therapies remains an important unmet need for patients with these muco-obstructive lung diseases. However, methods for sensitive visualization and quantitative assessment of immediate effects of therapeutic interventions on mucus clearance in vivo are lacking. In this study, we determined whether newly developed high-speed microscopic optical coherence tomography (mOCT) is sensitive to detect and compare in vivo effects of inhaled isotonic saline, hypertonic saline, and bicarbonate on mucus mobilization and clearance in Scnn1b-transgenic mice with muco-obstructive lung disease. In vivo mOCT imaging showed that inhaled isotonic saline-induced rapid mobilization of mucus that was mainly transported as chunks from the lower airways of Scnn1b-transgenic mice. Hypertonic saline mobilized a significantly greater amount of mucus that showed a more uniform distribution compared with isotonic saline. The addition of bicarbonate-to-isotonic saline had no effect on mucus mobilization, but also led to a more uniform mucus layer compared with treatment with isotonic saline alone. mOCT can detect differences in response to mucus-mobilizing interventions in vivo, and may thus support the development of more effective therapies for patients with muco-obstructive lung diseases.

Fiber optical shape sensing of flexible instruments for endovascular navigation.

PURPOSE: Endovascular aortic repair procedures are currently conducted with 2D fluoroscopy imaging. Tracking systems based on fiber Bragg gratings are an emerging technology for the navigation of minimally invasive instruments which can reduce the X-ray exposure and the used contrast agent. Shape sensing of flexible structures is challenging and includes many calculations steps which are prone to different errors. To reduce this errors, we present an optimized shape sensing model. METHODS: We analyzed for every step of the shape sensing process, which errors can occur, how the error affects the shape and how it can be compensated or minimized. Experiments were done with one multicore fiber system with 38 cm sensing length, and the effects of different methods and parameters were analyzed. Furthermore, we compared 3D shape reconstructions with the segmented shape of the corresponding CT scans of the fiber to evaluate the accuracy of our optimized shape sensing model. Finally, we tested our model in a realistic endovascular scenario by using a 3D printed vessel system created from patient data. RESULTS: Depending on the complexity of the shape, we reached an average error of 0.35-1.15 mm and maximal error of 0.75-7.53 mm over the whole 38 cm sensing length. In the endovascular scenario, we obtained an average and maximal error of 1.13 mm and 2.11 mm, respectively. CONCLUSION: The accuracies of the 3D shape sensing model are promising, and we plan to combine the shape sensing based on fiber Bragg gratings with the position and orientation of an electromagnetic tracking to obtain the located catheter shape.

Novel endoscope with increased depth of field for imaging human nasal tissue by microscopic optical coherence tomography.

Intravital microscopy (IVM) offers the opportunity to visualize static and dynamic changes of tissue on a cellular level. It is a valuable tool in research and may considerably improve clinical diagnosis. In contrast to confocal and non-linear microscopy, optical coherence tomography (OCT) with microscopic resolution (mOCT) provides intrinsically cross-sectional imaging. Changing focus position is not needed, which simplifies especially endoscopic imaging. For in-vivo imaging, here we are presenting endo-microscopic OCT (emOCT). A graded-index-lens (GRIN) based 2.75 mm outer diameter rigid endoscope is providing 1.5 - 2 µm nearly isotropic resolution over an extended field of depth. Spherical and chromatic aberrations are used to elongate the focus length. Simulation of the OCT image formation, suggests a better overall image quality in this range compared to a focused Gaussian beam. Total imaging depth at a reduced sensitivity and lateral resolution is more than 200 µm. Using a frame rate of 80 Hz cross-sectional images of concha nasalis were demonstrated in humans, which could resolve cilial motion, cellular structures of the epithelium, vessels and blood cells. Mucus transport velocity was successfully determined. The endoscope may be used for diagnosis and treatment control of different lung diseases like cystic fibrosis or primary ciliary dyskinesia, which manifest already at the nasal mucosa.