Preoperative ketamine administration for prevention of postoperative neurocognitive disorders after major orthopedic surgery in elderly patients: A multicenter randomized blinded placebo-controlled trial.

BACKGROUND: Preventive anesthetic impact on the high rates of postoperative neurocognitive disorders in elderly patients is debated. The Prevention of postOperative Cognitive dysfunction by Ketamine (POCK) study aimed to assess the effect of ketamine on this condition. METHODS: This is a multicenter, randomized, double-blind, interventional study. Patients ≥60 years undergoing major orthopedic surgery were randomly assigned in a 1:1 ratio to receive preoperative ketamine 0.5 mg/kg as an intravenous bolus (n = 152) or placebo (n = 149) in random blocks stratified according to the study site, preoperative cognitive status and age. The primary outcome was the proportion of objective delayed neurocognitive recovery (dNR) defined as a decline of one or more neuropsychological assessment standard deviations on postoperative day 7. Secondary outcomes included a three-month incidence of objective postoperative neurocognitive disorder (POND), as well as delirium, anxiety, and symptoms of depression seven days and three months after surgery. RESULTS: Among 301 patients included, 292 (97%) completed the trial. Objective dNR occurred in 50 (38.8%) patients in the ketamine group and 54 (40.9%) patients in the placebo group (OR [95% CI] 0.92 [0.56;1.51], p = 0.73) on postoperative day 7. Incidence of objective POND three months after surgery did not differ significantly between the two groups nor did incidence of delirium, anxiety, apathy, and fatigue. Symptoms of depression were less frequent in the ketamine group three months after surgery (OR [95%CI] 0.34 [0.13-0.86]). CONCLUSIONS: A single preoperative bolus of intravenous ketamine does not prevent the occurrence of dNR or POND in elderly patients scheduled for major orthopedic surgery. (Clinicaltrials.gov NCT02892916.).

The air conditioning in the nose of mammals depends on their mass and on their maximal running speed.

The nose of the mammals is responsible for filtering, humidifying, and heating the air before entering the lower respiratory tract. This conditioning avoids, notably, dehydration of the bronchial and alveolar mucosa. However, since this conditioning is not perfect, exercising in cold air can induce lung inflammation, both for human and non-human mammals. This work aims to compare the air conditioning in the noses of various mammals during inspiration. We build our study on computational fluid dynamics simulations of the heat exchanges in the lumen of the upper respiratory tract of these mammals. These simulations show that the efficiency of the air conditioning in the nose during inspiration does not relate only to the mass m of the mammal but also to its maximal running speed v. More precisely, the results allow establishing a scaling law relating the efficiency of air conditioning in the nose of mammals to the ratio v / log 10 ( m ) . The simulations also correlate the resistance to the flow in the nose to the efficiency of this air conditioning. The obtained scaling law allows predicting the air temperature at the top of the trachea during inspiration for nasal-breathing mammals, and thus notably for humans of various ages.

What Are the Key Anatomical Features for the Success of Nose-to-Brain Delivery? A Study of Powder Deposition in 3D-Printed Nasal Casts.

Nose-to-brain delivery is a promising way to improve the treatment of central nervous system disorders, as it allows the bypassing of the blood-brain barrier. However, it is still largely unknown how the anatomy of the nose can influence the treatment outcome. In this work, we used 3D printing to produce nasal replicas based on 11 different CT scans presenting various anatomical features. Then, for each anatomy and using the Design of Experiments methodology, we characterised the amount of a powder deposited in the olfactory region of the replica as a function of multiple parameters (choice of the nostril, device, orientation angle, and the presence or not of a concomitant inspiration flow). We found that, for each anatomy, the maximum amount of powder that can be deposited in the olfactory region is directly proportional to the total area of this region. More precisely, the results show that, whatever the instillation strategy, if the total area of the olfactory region is below 1500 mm2, no more than 25% of an instilled powder can reach this region. On the other hand, if the total area of the olfactory region is above 3000 mm2, the deposition efficiency reaches 50% with the optimal choice of parameters, whatever the other anatomical characteristics of the nasal cavity. Finally, if the relative difference between the areas of the two sides of the internal nasal valve is larger than 20%, it becomes important to carefully choose the side of instillation. This work, by predicting the amount of powder reaching the olfactory region, provides a tool to evaluate the adequacy of nose-to-brain treatment for a given patient. While the conclusions should be confirmed via in vivo studies, it is a first step towards personalised treatment of neurological pathologies.

Instrumented Flexible Glass Structure: A Bragg Grating Inscribed with Femtosecond Laser Used as a Bending Sensor.

Fused silica glass is a material with outstanding mechanical, thermal and optical properties. Being a brittle material, it is challenging to shape. In the last decade, the manufacturing of monolithic flexible mechanisms in fused silica has evolved with the femtosecond-laser-assisted etching process. However, instrumenting those structures is demanding. To address this obstacle, this article proposes to inscribe a Bragg Grating sensor inside a flexure and interface it with an optical fibre to record the strain using a spectrum analyser. The strain sensitivity of this Bragg Grating sensor is characterized at 1.2 pm/µÏµ (1 µÏµ = 1 microstrain). Among other applications, deformation sensing can be used to record a force. Its use as a micro-force sensor is estimated. The sensor resolution is limited by our recording equipment to 30 µN over a measurement range above 10 mN. This technology can offer opportunities for surgery applications or others where precision and stability in harsh environments are required.

Femtosecond pulse laser-engineered glass flexible structures instrumented with an in-built Bragg grating sensor.

The advent of near-infrared femtosecond pulse laser has enabled the highly-resolved manufacturing of micro/nano structures in various materials including glass. In this paper, we make use of an automated femtosecond laser system, so-called Femtoprint, to design a monolithic self-instrumented mechanism that we use for in-built strain sensing. To that aim, a flexible structure is designed and produced from a silica planar substrate. It has a flexural joint in which an optical waveguide and a Bragg grating have been directly inscribed using femtosecond pulse laser. The latter provides a non-destructive and non-intrusive measurement tool. The axial strain sensitivity of the in-built Bragg grating has been experimentally determined to be 1.22 pm/µ ϵ, while its temperature sensitivity is 10.51 pm/°C. The demonstration of such instrumented glass flexible mechanisms paves the way towards a new class of highly integrated sensors suitable for applications at the microscale or in harsh environments.

Strategies to Assess Occupational Exposure to Airborne Nanoparticles: Systematic Review and Recommendations.

In many industrial sectors, workers are exposed to manufactured or unintentionally emitted airborne nanoparticles (NPs). To develop prevention and enhance knowledge surrounding exposure, it has become crucial to achieve a consensus on how to assess exposure to airborne NPs by inhalation in the workplace. Here, we review the literature presenting recommendations on assessing occupational exposure to NPs. The 23 distinct strategies retained were analyzed in terms of the following points: target NPs, objectives, steps, "measurement strategy" (instruments, physicochemical analysis, and data processing), "contextual information" presented, and "work activity" analysis. The robustness (consistency of information) and practical aspects (detailed methodology) of each strategy were estimated. The objectives and methodological steps varied, as did the measurement techniques. Strategies were essentially based on NPs measurement, but improvements could be made to better account for "contextual information" and "work activity". Based on this review, recommendations for an operational strategy were formulated, integrating the work activity with the measurement to provide a more complete assessment of situations leading to airborne NP exposure. These recommendations can be used with the objective of producing homogeneous exposure data for epidemiological purposes and to help improve prevention strategies.

In vitro Evaluation of Paliperidone Palmitate Loaded Cubosomes Effective for Nasal-to-Brain Delivery.

Introduction: This work aimed to develop chitosan-coated cubosomal nanoparticles intended for nose-to-brain delivery of paliperidone palmitate. They were compared with standard and cationic cubosomal nanoparticles. This comparison relies on numerous classical in vitro tests and powder deposition within a 3D-printed nasal cast. Methods: Cubosomal nanoparticles were prepared by a Bottom-up method followed by a spray drying process. We evaluated their particle size, polydispersity index, zeta-potential, encapsulation efficiency, drug loading, mucoaffinity properties and morphology. The RPMI 2650 cell line was used to assess the cytotoxicity and cellular permeation. An in vitro deposition test within a nasal cast completed these measurements. Results: The selected chitosan-coated cubosomal nanoparticles loaded with paliperidone palmitate had a size of 305.7 ± 22.54 nm, their polydispersity index was 0.166 ± 0.022 and their zeta potential was +42.4 ± 0.2 mV. This formulation had a drug loading of 70% and an encapsulation efficiency of 99.7 ± 0.1%. Its affinity with mucins was characterized by a ΔZP of 20.93 ± 0.31. Its apparent permeability coefficient thought the RPMI 2650 cell line was 3.00E-05 ± 0.24E-05 cm/s. After instillation in a 3D-printed nasal cast, the fraction of the injected powder deposited in the olfactory region reached 51.47 ± 9.30% in the right nostril and 41.20 ± 4.59% in the left nostril, respectively. Conclusion: The chitosan coated cubosomal formulation seems to be the most promising formulation for nose-to-brain delivery. Indeed, it has a high mucoaffinity and a significantly higher apparent permeability coefficient than the two other formulations. Finally, it reaches well the olfactory region.

Controlled transitions between metastable states of 2D magnetocapillary crystals.

Magnetocapillary interactions between particles allow to self-assemble floating crystals along liquid interfaces. For a fixed number of particles, different states possessing different symmetrical features, known as metastable states, coexist. In this paper, we demonstrate how to trigger the transition from one state to another, either by rearranging the crystal, or by controlling its growth. First, we show that externally controlled magnetic fields can squeeze the entire crystal to induce structural modifications, that upon relaxation can lead to a modified state. Second, we propose localized laser-induced thermocapillary flows that can be used to guide new particles towards an existing crystal in a desired direction, thus favoring a particular resulting state. The control of the formation of metastable states is a key ingredient to functionalize such assemblies, paving the way to self-assembled microrobots.

Validation and Sensitivity analysis for a nasal spray deposition computational model.

Validating numerical models against experimental models of nasal spray deposition is challenging since many aspects must be considered. That being said, it is a critical step in the product development process of nasal spray devices. This work presents the validation process of a nasal deposition model, which demonstrates a high degree of consistency of the numerical model with experimental data when the nasal cavity is segmented into two regions but not into three. Furthermore, by modelling the flow as stationary, the computational cost is drastically reduced while maintaining quality of particle deposition results. Thanks to this reduction, a sensitivity analysis of the numerical model could be performed, consisting of 96 simulations. The objective was to quantify the impact of four inputs: the spray half cone angle, mean spray exit velocity, breakup length from the nozzle exit and the diameter of the nozzle spray device, on the three quantities of interest: the percentage of the accumulated number of particles deposited on the anterior, middle and posterior sections of the nasal cavity. The results of the sensitivity analysis demonstrated that the deposition on anterior and middle sections are sensitive to injection angle and breakup length, and the deposition on posterior section is only, but highly, sensitive to the injection velocity.

A Volume-Tuning Capillary Gripper That Enhances Handling Capabilities and Enables Testing of Micro-Components.

Capillary forces are shown to be extremely effective for micro-assembly and pick-and-place processes, especially for their ability to self-align the handled objects. However, in today's machines, micro-objects are submitted to high loads, such as compressions for the electrical testing of the micro-components, or inertial forces coming from the high accelerations of the machines. There, capillary grippers may show some limits. These issues, as well as the difficulty to perform precise visual inspections (due to the tilt of the handled micro-object that can occur after a perturbation, such as the displacement of the gripper), can all be solved by temporarily removing the liquid meniscus. Therefore, we present a novel volume-tuning capillary gripper that provides a solution to these limitations without adding additional significant complexities or changes to the existing pick-and-place machines. A multi-scale prototype was dimensioned and produced by using fast prototyping methods, such as a femtosecond laser-assisted chemical etching process for fused silica. Models bringing a deeper understanding of the subsystems are presented. The proof of concept was extensively tested. Its picking capabilities and enhancements of the handling capabilities during horizontal motions, as well as the repeatability of the tuning of the volume of liquid, are presented.

Instillation of a Dry Powder in Nasal Casts: Parameters Influencing the Olfactory Deposition With Uni- and Bi-Directional Devices.

Nose-to-brain delivery is a promising way to reach the central nervous system with therapeutic drugs. However, the location of the olfactory region at the top of the nasal cavity complexifies this route of administration. In this study, we used a 3D-printed replica of a nasal cavity (a so-called "nasal cast") to reproduce in vitro the deposition of a solid powder. We considered two different delivery devices: a unidirectional device generating a classical spray and a bidirectional device that relies on the user expiration. A new artificial mucus also coated the replica. Five parameters were varied to measure their influence on the powder deposition pattern in the olfactory region of the cast: the administration device, the instillation angle and side, the presence of a septum perforation, and the flow rate of possible concomitant inspiration. We found that the unidirectional powder device is more effective in targeting the olfactory zone than the bi-directional device. Also, aiming the spray nozzle directly at the olfactory area is more effective than targeting the center of the nasal valve. Moreover, the choice of the nostril and the presence of a perforation in the septum also significantly influence the olfactory deposition. On the contrary, the inspiratory flow has only a minor effect on the powder outcome. By selecting the more efficient administration device and parameters, 44% of the powder can reach the olfactory region of the nasal cast.

A Soft Pneumatic Two-Degree-of-Freedom Actuator for Endoscopy.

The rise of soft robotics opens new opportunities in endoscopy and minimally invasive surgery. Pneumatic catheters offer a promising alternative to conventional steerable catheters for safe navigation through the natural pathways without tissue injury. In this work, we present an optimized 6 mm diameter two-degree-of-freedom pneumatic actuator, able to bend in every direction and incorporating a 1 mm working channel. A versatile vacuum centrifugal overmolding method capable of producing small geometries with a variety of silicones is described, and meter-long actuators are extruded industrially. An improved method for fiber reinforcement is also presented. The actuator achieves bending more than 180° and curvatures of up to 0.1 mm-1. The exerted force remains below 100 mN, and with no rigid parts in the design, it limits the risks of damage on surrounding tissues. The response time of the actuator is below 300 ms and therefore not limited for medical applications. The working space and multi-channel actuation are also experimentally characterized. The focus is on the study of the influence of material stiffness on mechanical performances. As a rule, the softer the material, the better the energy conversion, and the stiffer the material, the larger the force developed at a given curvature. Based on the actuator, a 90 cm long steerable catheter demonstrator carrying an optical fiber is developed, and its potential for endoscopy is demonstrated in a bronchial tree phantom. In conclusion, this work contributes to the development of a toolbox of soft robotic solutions for MIS and endoscopic applications, by validating and characterizing a promising design, describing versatile and scalable fabrication methods, allowing for a better understanding of the influence of material stiffness on the actuator capabilities, and demonstrating the usability of the solution in a potential use-case.

Optimization and assessment of a novel gastric electrode anchoring system designed to be implanted by minimally invasive surgery.

A novel electrode anchoring design and its implantation procedure, aiming for a minimally invasive solution for gastric electrical stimulation, are presented. The system comprises an anchor made of a flexible body embedding two needle-shaped electrodes. The electrodes can easily switch from a parallel position - to pierce the stomach - to a diverging position - enabling them to remain firmly anchored into the muscular layer of the stomach. Key device parameters governing anchoring stability were assessed on a traction test bench, and optimal values were derived. The device was then implanted in six dogs by open surgery to assess its anchoring durability in vivo. Computed tomography images showed that the electrodes remained well placed within the dogs' gastric wall over the entire assessment period (more than one year). Finally, a prototype of a surgical tool for the minimally invasive device placement was manufactured, and the anchoring procedure was tested on a dog cadaver, providing the proof of concept of the minimally invasive implantation procedure. The use of our electrode anchoring system in long-term gastric electrical stimulation is promising in terms of implantation stability (the anchor withstands a force up to 0.81 N), durability (the anchor remains onto the stomach over one year) and minimal invasiveness of the procedure (the diameter of the percutaneous access is smaller than 12 mm). Moreover, the proposed design could have clinical applications in other hollow organs, such as the urinary bladder.

The importance of pre-formulation studies and of 3D-printed nasal casts in the success of a pharmaceutical product intended for nose-to-brain delivery.

This review aims to cement three hot topics in drug delivery: (a) the pre-formulation of new products intended for nose-to-brain delivery; (b) the development of nasal casts for studying the efficacy of potential new nose-to-brain delivery systems at the early of their development (pre-formulation); (c) the use of 3D printing based on a wide variety of materials (transparent, biocompatible, flexible) providing an unprecedented fabrication tool towards personalized medicine by printing nasal cast on-demand based on CT scans of patients. This review intends to show the links between these three subjects. Indeed, the pathway selected to administrate the drug to the brain not only influence the formulation strategies to implement but also the design of the cast, to get the most convincing measures from it. Moreover, the design of the cast himself influences the choice of the 3D-printing technology, which, in its turn, bring more constraints to the nasal replica design. Consequently, the formulation of the drug, the cast preparation and its realisation should be thought of as a whole and not separately.

Optimization of Phase-Change Material-Elastomer Composite and Integration in Kirigami-Inspired Voxel-Based Actuators.

Phase-change material-elastomer composite (PCMEC) actuators are composed of a soft elastomer matrix embedding a phase-change fluid, typically ethanol, in microbubbles. When increasing the temperature, the phase change in each bubble induces a macroscopic expansion of the matrix. This class of actuators is promising for soft robotic applications because of their high energy density and actuation strain, and their low cost and easy manufacturing. However, several limitations must be addressed, such as the high actuation temperature and slow actuation speed. Moreover, the lack of a consistent design approach limits the possibility to build PCMEC-based soft robots able to achieve complex tasks. In this work, a new approach to manufacture PCMEC actuators with different fluid-elastomer combinations without altering the quality of the samples is proposed. The influence of the phase-change fluid and the elastomer on free elongation and bending is investigated. We demonstrate that choosing an appropriate fluid increases the actuation strain and speed, and decreases the actuation temperature compared with ethanol, allowing PCMECs to be used in close contact with the human body. Similarly, by using different elastomer materials, the actuator stiffness can be modified, and the experimental results showed that the curvature is roughly proportional to the inverse of Young's modulus of the pure matrix. To demonstrate the potential of the optimized PCMECs, a kirigami-inspired voxel-based design approach is proposed. PCMEC cubes are molded and reinforced externally by paper. Cuts in the paper induce anisotropy into the structure. Elementary voxels deforming according to the basic kinematics (bending, torsion, elongation, compression and shear) are presented. The combination of these voxels into modular and reconfigurable structures could open new possibilities towards the design of flexible robots able to perform complex tasks.

A consensus research agenda for optimising nasal drug delivery.

Nasal drug delivery has specific challenges which are distinct from oral inhalation, alongside which it is often considered. The next generation of nasal products will be required to deliver new classes of molecule, e.g. vaccines, biologics and drugs with action in the brain or sinuses, to local and systemic therapeutic targets. Innovations and new tools/knowledge are required to design products to deliver these therapeutic agents to the right target at the right time in the right patients. We report the outcomes of an expert meeting convened to consider gaps in knowledge and unmet research needs in terms of (i) formulation and devices, (ii) meaningful product characterization and modeling, (iii) opportunities to modify absorption and clearance. Important research questions were identified in the areas of device and formulation innovation, critical quality attributes for different nasal products, development of nasal casts for drug deposition studies, improved experimental models, the use of simulations and nasal delivery in special populations. We offer these questions as a stimulus to research and suggest that they might be addressed most effectively by collaborative research endeavors.

Pick up and release of micro-objects: a motion-free method to change the conformity of a capillary contact.

We propose a new 3D-printed capillary gripper equipped with a textured surface for motion-free release. The gripper classically picks up micro-objects thanks to the capillary forces induced by a liquid bridge. Micro-objects are released by decreasing the volume of this bridge through evaporation. The latter can be either natural or speeded up by a heating source (an IR laser or the Joule effect). The volume reduction changes the conformity of the contact between the gripper and the object. We analyze the gripper performance and the capillary force generated, and then we rationalize the release mechanism by defining the concept of contact conformity in the context of capillary forces.

Design, characterization and optimization of a soft fluidic actuator for minimally invasive surgery.

PURPOSE: In minimally invasive surgery and endoscopy, the rise of soft robotics, using materials of similar softness as biological soft tissues, opens many new opportunities. Soft actuated catheters could become an alternative to current steerable catheters, by minimizing the risk of damage to surrounding tissues while enhancing the possibilities to navigate in confined space and to reach remote locations. Fluidic actuators present the advantage to be safe, since they do not require rigid parts nor voltage, to be lightweight, and to allow the reduction of the number of parts needed for a given movement. This work presents the design, development and characterization of a soft fluidic bending actuator for a steerable catheter. METHODS: A silicone prototype of 5 mm diameter has been designed. It has one degree of freedom in bending and achieves a radius of curvature below 10 mm. A numerical model has been developed and compared to the experimental results. RESULTS: Despite an overestimation of the bending, the numerical model properly captures the behaviour of the actuator. This allowed to identify and validate the key design parameters of the actuator, namely the ratio between the pressure channel surface and the actuator cross-section surface. Based on the results, an optimized design has been developed and numerically implemented. The miniaturization and the potential to carry devices with non-negligible bending stiffness have also been discussed. CONCLUSION: In this work, a proof of concept of a soft fluidic actuator for a steerable catheter has been designed, developed and characterized. It showed promising results concerning the feasibility of a miniaturized actuator with two degrees of freedom.

Rupture of a Liquid Bridge between a Cone and a Plane.

In this work, a systematic experimental study of the rupture of an axially symmetric liquid bridge between a cone and a plane was performed, with focus on the volume distribution after break up. A model based on the Young-Laplace equation is presented, and its solutions are compared to experimental data. Cones and conical cavities with different aperture angles were used in our experiments. We found that this aperture influences the potential pinning of the contact line, the meniscus shape, and therefore the liquid transfer. For half aperture angles α < 70°, where no pinning was observed, the liquid bridge slips off from the cone and almost no transfer to the cone is observed. However, at α > 70°, contact line pinning on the cone induces a net liquid transfer to the cone at rupture. In the case of conical cavities, a maximum of liquid transfer is observed for at α = 110°. The distance at which the rupture of the liquid bridge occurs is also discussed. The model can fairly predict the transfer ratio and the rupture height of the liquid bridge.

Microscale Surface Tension and its Applications.

More than 200 years since the earliest scientific investigations by Young, Laplace and Plateau, liquid surface tension is still the object of thriving fundamental and applied research [...].