Preliminary Assessment of an Ambulatory Device Dedicated to Upper Airway Muscle Training in Patients With Sleep Apnea: Proof-of-Concept Study.

BACKGROUND: Obstructive sleep apnea/hypopnea syndrome (OSAHS) is a prevalent condition affecting a substantial portion of the global population, with its prevalence increasing over the past 2 decades. OSAHS is characterized by recurrent upper airway (UA) closure during sleep, leading to significant impacts on quality of life and heightened cardiovascular and metabolic morbidity. Despite continuous positive airway pressure (CPAP) being the gold standard treatment, patient adherence remains suboptimal due to various factors, such as discomfort, side effects, and treatment unacceptability. OBJECTIVE: Considering the challenges associated with CPAP adherence, an alternative approach targeting the UA muscles through myofunctional therapy was explored. This noninvasive intervention involves exercises of the lips, tongue, or both to improve oropharyngeal functions and mitigate the severity of OSAHS. With the goal of developing a portable device for home-based myofunctional therapy with continuous monitoring of exercise performance and adherence, the primary outcome of this study was the degree of completion and adherence to a 4-week training session. METHODS: This proof-of-concept study focused on a portable device that was designed to facilitate tongue and lip myofunctional therapy and enable precise monitoring of exercise performance and adherence. A clinical study was conducted to assess the effectiveness of this program in improving sleep-disordered breathing. Participants were instructed to perform tongue protrusion, lip pressure, and controlled breathing as part of various tasks 6 times a week for 4 weeks, with each session lasting approximately 35 minutes. RESULTS: Ten participants were enrolled in the study (n=8 male; mean age 48, SD 22 years; mean BMI 29.3, SD 3.5 kg/m2; mean apnea-hypopnea index [AHI] 20.7, SD 17.8/hour). Among the 8 participants who completed the 4-week program, the overall compliance rate was 91% (175/192 sessions). For the tongue exercise, the success rate increased from 66% (211/320 exercises; SD 18%) on the first day to 85% (272/320 exercises; SD 17%) on the last day (P=.05). AHI did not change significantly after completion of training but a noteworthy correlation between successful lip exercise improvement and AHI reduction in the supine position was observed (Rs=-0.76; P=.03). These findings demonstrate the potential of the device for accurately monitoring participants' performance in lip and tongue pressure exercises during myofunctional therapy. The diversity of the training program (it mixed exercises mixed training games), its ability to provide direct feedback for each exercise to the participants, and the easy measurement of treatment adherence are major strengths of our training program. CONCLUSIONS: The study's portable device for home-based myofunctional therapy shows promise as a noninvasive alternative for reducing the severity of OSAHS, with a notable correlation between successful lip exercise improvement and AHI reduction, warranting further development and investigation.

Microflow sensing and control using an in-channel birefringent biomembrane.

This study describes the function, optimization, and demonstration of a new class of passive, low-cost microfluidic flow meters based on birefringent chitosan biomembranes analyzed by polarized microscopy. We subjected the membrane to dynamic flow conditions while monitoring the real-time response of its optical properties. We obtained figures of merit, including the linear response operating range (0 to 65 µL min-1), minimum response time (250 ms), sensitivity (2.03% × 10-3 µL-1 min), and minimum sensor longevity (1 week). In addition, possible sources of interference were identified. Finally, we demonstrate the membrane as a low-cost flow rate measurement device for the close loop control of a commercial pressure-driven pump. Preliminary experiments using a basic PID controller with the membrane-based flow rate measurement device showed that stable control could be achieved and the system could reach steady-state behavior in less than 15 seconds. Analysis of fundamental limits to sensor response time indicate the potential for faster steady-state behaviour.

Improving the 3D Printability of Sugar Glass to Engineer Sacrificial Vascular Templates.

A prominent obstacle in scaling up tissue engineering technologies for human applications is engineering an adequate supply of oxygen and nutrients throughout artificial tissues. Sugar glass has emerged as a promising 3D-printable, sacrificial material that can be used to embed perfusable networks within cell-laden matrices to improve mass transfer. To characterize and optimize a previously published sugar ink, we investigated the effects of sucrose, glucose, and dextran concentration on the glass transition temperature (Tg), printability, and stability of 3D-printed sugar glass constructs. We identified a sucrose ink formulation with a significantly higher Tg (40.0 ± 0.9°C) than the original formulation (sucrose-glucose blend, Tg = 26.2 ± 0.4°C), which demonstrated a pronounced improvement in printability, resistance to bending, and final print stability, all without changing dissolution kinetics and decomposition temperature. This formulation allowed printing of 10-cm-long horizontal cantilever filaments, which can enable the printing of complex vascular segments along the x-, y-, and z-axes without the need for supporting structures. Vascular templates with a single inlet and outlet branching into nine channels were 3D printed using the improved formulation and subsequently used to generate perfusable alginate constructs. The printed lattice showed high fidelity with respect to the input geometry, although with some channel deformation after alginate casting and gelation-likely due to alginate swelling. Compared with avascular controls, no significant acute cytotoxicity was noted when casting pancreatic beta cell-laden alginate constructs around improved ink filaments, whereas a significant decrease in cell viability was observed with the original ink. The improved formulation lends more flexibility to sugar glass 3D printing by facilitating the fabrication of larger, more complex, and more stable sacrificial networks. Rigorous characterization and optimization methods for improving sacrificial inks may facilitate the fabrication of functional cellular constructs for tissue engineering, cellular biology, and other biomedical applications.

A spectIR-fluidic reactor for monitoring fast chemical reaction kinetics with on-chip attenuated total reflection Fourier transform infrared spectroscopy.

Microfluidics has emerged as a powerful technology with diverse applications in microbiology, medicine, chemistry, and physics. While its potential for controlling and studying chemical reactions is well recognized, the extraction and analysis of useful chemical information generated within microfluidic devices remain challenging. This is mainly due to the limited tools available for in situ measurements of chemical reactions. In this study, we present a proof-of-concept spectIR-fluidic reactor design that combines microfluidics with Fourier transform infrared (FTIR) spectroscopy for in situ kinetic studies of fast reactions. By integrating a multi-ridge silicon attenuated total reflection (ATR) wafer into the microfluidic device, we enable multi-point measurements for precise reaction time monitoring. As such, this work establishes a validated foundation for studying fast chemical reactions using on-chip ATR-FTIR spectroscopy in a microfluidic reactor environment, which enables simultaneous monitoring of reagents, intermediates, and products using a phosphate proton transfer reaction. The spectIR-fluidic reactor platform offers customizable designs, allowing for the investigation of reactions with various time scales, and has the potential to significantly advance studies exploring reaction mechanisms and optimization.

SpectIR-fluidics: completely customizable microfluidic cartridges for high sensitivity on-chip infrared spectroscopy with point-of-application studies on bacterial biofilms.

We present a generalizable fabrication method for a new class of analytical devices that merges virtually any microfluidic design with high-sensitivity on-chip attenuated total reflection (ATR) sampling using any standard Fourier transform infrared (FTIR) spectrometer. Termed "spectIR-fluidics", a major design feature is the integration of a multi-groove silicon ATR crystal into a microfluidic device, compared with previous approaches in which the ATR surface served as a structural support for the entire device. This was accomplished by the design, fabrication, and aligned bonding of a highly engineered ATR sensing layer, which con```tains a seamlessly embedded ATR crystal on the channel side and an optical access port that matched the spectrometer light path characteristics at the device exterior. The refocused role of the ATR crystal as a dedicated analytical element, combined with optimized light coupling to the spectrometer, results in limits of detection as low as 540 nM for a D-glucose solution, arbitrarily complex channel features that are fully enclosed, and up to 18 world-to-chip connections. Three purpose-built spectIR-fluidic cartridges are used in a series of validation experiments followed by several point-of-application studies on biofilms from the gut microbiota of plastic-consuming insects using a small portable spectrometer.

A Nanoparticle Ink Allowing the High Precision Visualization of Tissue Engineered Scaffolds by MRI.

Hydrogels are widely used as cell scaffolds in several biomedical applications. Once implanted in vivo, cell scaffolds must often be visualized, and monitored overtime. However, cell scaffolds appear poorly contrasted in most biomedical imaging modalities such as magnetic resonance imaging (MRI). MRI is the imaging technique of choice for high-resolution visualization of low-density, water-rich tissues. Attempts to enhance hydrogel contrast in MRI are performed with "negative" contrast agents that produce several image artifacts impeding the delineation of the implant's contours. In this study, a magnetic ink based on ultra-small iron oxide nanoparticles (USPIONs; <5 nm diameter cores) is developed and integrated into biocompatible alginate hydrogel used in cell scaffolding applications. Relaxometric properties of the magnetic hydrogel are measured, as well as biocompatibility and MR-visibility (T1 -weighted mode; in vitro and in vivo). A 2-week MR follow-up study is performed in the mouse model, demonstrating no image artifacts, and the retention of "positive" contrast overtime, which allows very precise delineation of tissue grafts with MRI. Finally, a 3D-contouring procedure developed to facilitate graft delineation and geometrical conformity assessment is applied on an inverted template alginate pore network. This proof-of-concept establishes the possibility to reveal precisely engineered hydrogel structures using this USPIONs ink high-visibility approach.

Biofabrication of Sodium Alginate Hydrogel Scaffolds for Heart Valve Tissue Engineering.

Every year, thousands of aortic valve replacements must take place due to valve diseases. Tissue-engineered heart valves represent promising valve substitutes with remodeling, regeneration, and growth capabilities. However, the accurate reproduction of the complex three-dimensional (3D) anatomy of the aortic valve remains a challenge for current biofabrication methods. We present a novel technique for rapid fabrication of native-like tricuspid aortic valve scaffolds made of an alginate-based hydrogel. Using this technique, a sodium alginate hydrogel formulation is injected into a mold produced using a custom-made sugar glass 3D printer. The mold is then dissolved using a custom-made dissolving module, revealing the aortic valve scaffold. To assess the reproducibility of the technique, three scaffolds were thoroughly compared. CT (computed tomography) scans showed that the scaffolds respect the complex native geometry with minimal variations. The scaffolds were then tested in a cardiac bioreactor specially designed to reproduce physiological flow and pressure (aortic and ventricular) conditions. The flow and pressure profiles were similar to the physiological ones for the three valve scaffolds, with small variabilities. These early results establish the functional repeatability of this new biofabrication method and suggest its application for rapid fabrication of ready-to-use cell-seeded sodium alginate scaffolds for heart valve tissue engineering.

Scanning Aperture Approach for Spatially Selective ATR-FTIR Spectroscopy: Application to Microfluidics.

We present a novel spectroscopy accessory that can easily convert any Fourier transform infrared (FTIR) spectrometer into a fully automated mapping and assaying system. The accessory uses a multiridge attenuated total reflection (ATR) wafer as the sensing element coupled with a moving aperture that is used to select the regions of interest on the wafer. In this demonstration, the accessory is combined with a series of parallel micropatterned channels, which are positioned co-linear with the light-coupling ridges on the opposite side of the ATR wafer. The ATR spectroscopy microfluidic assay accessory (ASMAA) was used in continuous mapping mode to scan perpendicular to the ATR ridges, revealing complex but repeatable oscillations in the spectral intensities. To understand this behavior, the light path through the optical components was simulated with consideration of the aperture position, ridge-to-channel alignment, and excitation beam profile. With this approach, the simulation reproduced the experimental mapping results and provided evidence that the measurement position and area changed with the aperture position. To demonstrate the assay mode, we obtained spectra along the centerline of individual microchannels and determined noise baselines and limits of detection.

An in vitro Perfused Macroencapsulation Device to Study Hemocompatibility and Survival of Islet-Like Cell Clusters.

Transplantation of hydrogel-encapsulated pancreatic islets is a promising long-term treatment for type 1 diabetes that restores blood glucose regulation while providing graft immunoprotection. Most human-scale islet encapsulation devices that rely solely on diffusion fail to provide sufficient surface area to meet islet oxygen demands. Perfused macroencapsulation devices use blood flow to mitigate oxygen limitations but increase the complexity of blood-device interactions. Here we describe a human-scale in vitro perfusion system to study hemocompatibility and performance of islet-like cell clusters (ILCs) in alginate hydrogel. A cylindrical perfusion device was designed for multi-day culture without leakage, contamination, or flow occlusion. Rat blood perfusion was assessed for prothrombin time and international normalized ratio and demonstrated no significant change in clotting time. Ex vivo perfusion performed with rats showed patency of the device for over 100 min using Doppler ultrasound imaging. PET-CT imaging of the device successfully visualized metabolically active mouse insulinoma 6 ILCs. ILCs cultured for 7 days under static conditions exhibited abnormal morphology and increased activated caspase-3 staining when compared with the perfused device. These findings reinforce the need for convective transport in macroencapsulation strategies and offer a robust and versatile in vitro system to better inform preclinical design.

A New Approach Based on a Multiobjective Evolutionary Algorithm for Accurate Control of Flow Rate and Blood Pressure in Cardiac Bioreactors.

PURPOSE: Accurately reproducing physiological and time-varying variables in cardiac bioreactors is a difficult task for conventional control methods. This paper presents a new controller based on a genetic algorithm for the control of a cardiac bioreactor dedicated to the study and conditioning of heart valve substitutes. METHODS: A multi-objective genetic algorithm was designed to obtain an accurate simultaneous reproduction of physiological periodic time functions of the three most relevant variables characterizing the blood flow in the aortic valve. These three controlled variables are the flow rate and the pressures upstream and downstream of the aortic valve. RESULTS: Experimental results obtained with this new algorithm showed an accurate dynamic reproduction of these three controlled variables. Moreover, the controller can react and adapt continuously to changes happening over time in the cardiac bioreactor, which is a major advantage when working with living biological valve substitutes. CONCLUSION: The strong non-linear interaction that exists between the three controlled variables makes it difficult to obtain a precise control of any of these, let alone all three simultaneously. However, the results showed that this new control algorithm can efficiently overcome such difficulties. In the particular field of bioreactors reproducing the cardiovascular environment, such a flexible, versatile and accurate reproduction of these three interdependent controlled variables is unprecedented.

Linear Scanning ATR-FTIR for Chemical Mapping and High-Throughput Studies of Pseudomonas sp. Biofilms in Microfluidic Channels.

A fully automated linear scanning attenuated total reflection (ATR) accessory is presented for Fourier transform infrared (FTIR) spectroscopy. The approach is based on the accurate displacement of a multibounce ATR crystal relative to a stationary infrared beam. To ensure accurate positioning and to provide a second sample characterization mode, a custom-built microscope was integrated into the system and the computerized work flow. Custom software includes automated control and measurement routines with a straightforward user interface for selecting parameters and monitoring experimental progress. This cost-effective modular system can be implemented on any research-grade spectrometer with a standard sample compartment for new bioanalytical chemistry studies. The system was validated and optimized for use with microfluidic flow cells containing growing Pseudomonas sp. bacterial biofilms. The complementarity among the scan positioning accuracy, measurement spatial resolution, and the microchannel dimensions paves the way for parallel biological assays with real-time control over environmental parameters and minimal manual labor. By rotating the channel orientation relative to the beam path, the system could also be used for acquisition of linear biochemical maps and stitched microscope images along the channel length.

Sugar glass fugitive ink loaded with calcium chloride for the rapid casting of alginate scaffold designs.

Alginate-based hydrogels are widely used for the development of biomedical scaffolds in regenerative medicine. The use of sugar glass as a sacrificial template for fluidic channels fabrication within alginate scaffolds remains a challenge because of the premature dissolution of sugar by the water contained in the alginate as well as the relatively slow internal gelation rate of the alginate. Here, a new and simple method, based on a sugar glass fugitive ink loaded with calcium chloride to build sacrificial molds, is presented. We used a dual calcium cross-linking process by adding this highly soluble calcium source in the printed sugar, thus allowing the rapid gelation of a thin membrane of alginate around the sugar construct, followed by the addition of calcium carbonate and gluconic acid δ-lactone to complete the process. This innovative technique results in the rapid formation of "on-demand" alginate hydrogel with complex fluidic channels that could be used in biomedical applications such as highly vascularized scaffolds promoting pathways for nutrients and oxygen to the cells.