The blood–brain barrier (BBB) is a sophisticated structure whose full functionality is required for maintaining the executive functions of the central nervous system (CNS). Tight control of transport across the barrier means that most drugs, particularly large size, which includes powerful biologicals, cannot reach their targets in the brain. Notwithstanding the remarkable advances in characterizing the cellular nature of the BBB and consequences of BBB dysfunction in pathology , it remains challenging to deliver drugs to the CNS. Herein, we outline the basic architecture and key molecular constituents of the BBB. In addition, we review the current status of approaches that are being explored to temporarily open the BBB in order to allow accumulation of therapeutics in the CNS. Undoubtedly, the major concern in field is whether it is possible to open the BBB in a meaningful way without causing negative consequences. In this context, we have also listed few other important key considerations that can improve our understanding about the dynamics of the BBB. The complex organization of the blood–brain barrier (BBB) is not only attributed for the exchange of passive diffusion/efflux of solutes in the blood or for the active transport of nutrients to the brain, but also for regulating the migration of circulating immune cells. Of interest, the dynamic association of microvascular endothelial cells (ECs) with pericytes, astrocytes and microglia, together with their specialized structural composition of tight junctions (TJs)/adherens junction (Ajs) form the main interface for intracellular signaling. A wealth of literature published during the last decades has evidenced a strong correlation between BBB dysfunction, alteration of TJ complexes and progression of multiple CNS diseases . Given that BBB alterations have been identified in major depressive disorder, bipolar disorder and schizophrenia, a recent study discussed that gender differences exist in inflammation-induced loss of BBB integrity and that BBB-related transcriptional changes occur differently in men and women . Under cNEK1) gene, which encodes a serine/threonine kinase, are involved in human developmental disorders and amyotrophic lateral sclerosis (ALS). A recent study showed that the metabolic dysfunction in Nek1 deficient cells reduces the levels of A20 (an important ubiquitin editing enzyme) to promote the activation of RIPK1 (Receptor Interacting Serine/Threonine Kinase 1), necroptosis of CD31+ endothelial cells and BBB damage [ABCB1) gene expressed highly at BBB, and a study has shown that single nucleotide polymorphisms (SNPs) in ABCB1 may contribute to the progression of amyloid beta deposition in the brain [Similarly, it has been shown that a possible transport of activated protein C across the mouse blood–brain barrier requires an efficient Endothelial protein C receptor .There haB damage . There hhe brain . In conthe brain . In facthe brain . Besideshe brain . Here, ihe brain , 13. Reche brain .Recently, a study unraveled a number of key players involved in the interaction between breast cancer cells (BCCs) and BBB endothelial cells that underlie BBB alterations and transendothelial migration of malignant cells . Over th, ex vivo (lab cultured resected tissue), in silico (computer models) and, in vitro. In vitro models are a bioengineering effort to mimic the tissue of interest based on the triad stem cells, extracellular matrix, and soluble factors. Applied to the development of in vitro neurovascularity unit, this concept has resulted in several models that can recapitulate main features of BBB, with the most recent advances and developments being reviewed in the following sub-section.The concept of in vitro models is born with the surge of tissue engineering, despite the previous use of cells onto plastic surfaces for early cytotoxicity testing of compounds of interest. Modelling is the ability to mirror the characteristics of a complex system, with the purpose of extracting information from it. In health sciences there are four main types of models: in vivo -like challenge [In recent years, the interest in the development of in vitro models to recapitulate the human BBB has increased. The search for models that can reduce the number of animals used for research has led to the development of new techniques and contributed to the growth of the biotechnology industry, particularly the industry of microphysiological models (MPS). The main application of MPS is in the development of new drugs or new drug delivery strategies. Following this trend, several high-profile investigators have pushed the use of these models and proposed a roadmap for the integration of MPS in the drug development industry . The crehallenge . The usehallenge . In vitrhallenge .Organoids are self-organized cellular structures that can be derived directly from patient tissue or through the use of developmental biology. Organoids exhibit characteristics of several organs such as the pancreas, gut, retina, and brain . Researc2, these organoids are comparable to other BBB models [The presence of a BBB in organoids is crucial for the design of a fully biomimetic drug or disease testing platform. The need for these features has been recognised by the leaders in the field and was reviewed extensively in 2018 . VasculaB models .BBB organoids can be fused with cerebral organoids to form neurovascular structures. These structures exhibit BBB features such as basement membrane specific proteins and vessel-like morphology whilst cerebral organoids express standard neuronal markers . NeurovaInnovations in the biomedical field that do not follow the state-of-art biological standards, usually showcase a technological progress or methodology that makes them more translatable, due to the robustness of the process, a monitoring capacity or the relevance of the application of the model itself. Since the organoids’ field is still young and requires maturation, applied works often follow simpler biological approaches to hint at new models, from which straightforward outcomes can be extracted. Examples of this paradigm are models that test glioblastoma’s drug sensitivity and therapy strategies  or Sars-However, most drug tests performed using BBB platforms focus on advanced drug delivery strategies, such as summarized in Table In vitro BBB modeling has clear advantages such as cost effectiveness and high throughput, but due to the complexity of the BBB, the available models are far from perfect and thus animal models are still a mainstay of research into the physiology, pathology and controlled manipulation of the BBB. In vivo models provide unique insight into the cellular, morphological and functional properties and barrier permeability in healthy and disease-damaged brains. Of note is that some evidence suggests functional differences between human and rodent BBB with the latter characterized by lower threshold for disruption . NumerouRapoport first described in the early 1970s that infusion of hypertonic substances such as arabinose, urea or mannitol causes endothelial cells to contract, thereby increasing vascular permeability, effectively resulting in transient opening of the BBB . Since tBBB breach was assessed by intravenous injection of Evans blue in Ringer solution immediately after OBBBO and demonstrated cerebral accumulation of the blue dye. In 1973 Brightman et al. used electron microscopy to show that 3 M urea led to opening of endothelial tight junctions . Burks eMembrane active molecules are a group of substances that interact with cell membranes leading to their destabilization and increased permeability . Sarkar Vascular endothelial growth factor (VEGF), also known as vascular permeability factor, is a signaling polypeptide produced by many cells that regulates function of blood vessels and is best known for stimulating the formation of blood vessels . VEGF, wOne of the recent advances in BBB opening is the mechanical destabilization of tight junctions within the cerebral endothelium. The technique uses low-frequency ultrasound waves in combination with intravenously injected microbubbles. Microbubbles in cerebral vasculature amplify local cavitation resulting in BBB breach. This method is spatially selective, relatively straight forward and non-invasive. The first reports of the use of this method date back to the beginning of the twenty-first century. In a study by Hynynen et al. in 2005, the feasibility of transmitting focused ultrasound (FUS) energy across the intact rabbit skull was assessed . The groWhile brain cancer is the most frequent application for FUS BBBO it has been used to enhance drug delivery in other models of neurological diseases. Kinoshita et al. used FUS to target delivery of polyclonal antibodies against the extracellular domain of the dopamine D4 receptor to the brain. Immunohistochemistry confirmed a positive signal of anti-rabbit IgG in the sonicated area in the ipsilateral hemisphere . Alzheim, adapted from [Multiple methods for BBB opening have been explored, however, all of them showed limitations in terms of their successful implementation in the clinical context –100. Amo2ted from , 102). Fted from , antibodted from , neural ted from , AAV-basted from , nanoparted from , and cheted from  has beented from –113. Furted from . FUS hasted from . As a meted from  and Alzhted from . A recented from . Similarted from . Though ted from . Intra-aInterestingly, intra-arterial administration is still considered far superior compared to other contemporary methods , especially from a physiological perspective. Considering the preferential retention of administered substances in brain tissue, pharmacokinetic optimizations have favored intra-arterial over intravenous delivery approaches , 121. A Substantial efforts have been made to tune properties of therapeutic agents to facilitate their penetration across the BBB. Approaches used to breach the BBB strongly depend on the size of the molecule to be delivered. Some small molecules are capable of passively diffusing through the BBB, and there is intensive work to improve their properties in this regard. Other small molecules use active systems in order to pass through the BBB. Large molecules are not able to passively cross the BBB, thus approaches have been made to fit large molecules into existing transport systems. Cellular therapeutics require diapedesis to extravasate to the brain parenchyma, and there are several ways to achieve this: through genetic, epigenetic, chemical and physical engineering and pre-conditioning of potential cellular products. Noteworthy, the penetrating therapeutic agents also need to avoid being actively effluxed back to the circulation by a guarding system of pumps and transporters. Thus, the biological, chemical and physical barriers are complex and delivery of a wide range of therapeutic agents to the brain remains difficult. Efforts towards increasing penetration of small molecules are centered around three mechanisms: increased diffusion, decreased efflux and better exploitation of transporters . The lipWhile drugs with a large molecular size are unable to cross the BBB, several potential strategies exist to facilitate their delivery into the brain. These include: (A) pharmacologic formulation, such as exosomal encapsulation or cellular carriers for transcytotic transport across BBB; (B) conjugation with ligands for biological transporters and receptors in the BBB and (C) temporary disruption of BBB as discussed earlier. Transcytosis is a process of transport of large proteins, exosomes, microbes, viruses, bacteria or mammalian cells such as immune cells into the brain . The effStem cell therapies for neurological diseases are challenging to deliver to the brain due to the barrier functions of the BBB. The poor transport of exogenous cells across the BBB limits the efficacy of intravascular administration. How stem cells migrate across the BBB is a controversial topic. Still, there are many reported similarities to immune cell infiltration, including rolling on and adhesion to the endothelium and transmigration across the BBB. The BBB becomes compromised during brain inflammation and injury, and cellular trafficking through the BBB is significantly upregulated . CirculaThe adhesion molecule-dependent process of diapedesis described in leukocytes has been long recognized. Leukocytes extravasate through the ligand-receptor interactions. Among them, the very late antigen (VLA)-4–VCAM1 axis is a well-known contributor to the diapedesis of leukocytes. VLA-4 is expressed on the surface of cells, while VCAM1 is present on the endothelium. The VLA-4/VCAM-1 axis and its role in the diapedesis of transplanted stem cells have been described by Gavina et al. . They deAnother strategy to increase the transmigration of cells into brain tissue after intravascular infusion is to modify stem cells with factors that enhance chemokine receptor expression. Such a procedure has been shown to increase the number of cells homing to the brain. The critical role of the C–C chemokine ligand 2 (CCL2) and C–C chemokine receptor 2 (CCR2) in the targeted homing of stem cells was demonstrated by Guzman group . After iAs aforementioned, the major concern in field is whether it is possible to open the BBB in a meaningful way without causing negative consequences. To achieve this, it is particularly important to broaden our understanding about the dynamics of the BBB. In this context, a few key considerations we proposed are: (1) whether the ensuing inflammation caused by BBB opening will be beneficial or detrimental to the brain microenvironment, (2) as the core structure of tight junction barriers are not static rather highly dynamic that allows discrete trafficking under physiological or pathological stresses, so whether areas of the BBB with different densities of tight junctions (lipid-protein composition) should be targeted as high-permeability gateways, (3) how can we empirically analyze the BBB based animal models to predict the human response accurately, (4) can we quantitatively model the interaction between BBB transport and glymphatic clearance (net fluid flow inward through arteries and outward through veins), (5) Whether transient transcriptional changes with long-term effects are to be expected, especially when conducting locus-specific BBB studies, and (6) since concentrations of several molecules in the CNS are subject to circadian oscillations/rhythms, therefore, we do need to check the permeability/efflux of our current compounds according to this circadian clock.Research into drug development targeting the CNS is complex and it is uncertain which approach will be successful. The systemic problems in the drug development industry are aggravated by the inaccessibility and sensitivity of brain tissue, while it remains the most suitable tissue to develop novel and innovative drug delivery systems. Despite the urgency of the field in addressing the problems in drug delivery to the CNS, methodologic divergences have been faced by the field for decades. The widespread use of animal models, the most commonly used model system in pre-clinical trials, is currently being questioned due to discrepancy in research findings from animals and human patients, particularly in BBB transposing systems. These translational problems have contributed to improvement of existing animal models and have fueled the development of human neurovascular models that mimic native neurovascularity more closely. In the search for in vivo models, tissue engineering has focused on tissue organoids, leading to the emergence of a burst of brain organoid models in recent years. Nonetheless, technological innovation and disease-modeling are currently still performed in assembled structures, using a bottom-up approach that has been used in the field for more than 30 years. In the next few years, hybrid strategies integrating disease-specific assembled structures and organoids-on-chip will become an integral part of pre-clinical and clinical research. This trend will guide the field towards effective precision medicine, with patient-derived organoids resembling the native tissue, integrated in a robust and reproducible BBB vascular network, achieving high statistical significance.


By the decision of the Polish Government, all persons arriving in the territory of the Republic of Poland after the commencement of the Russian aggression against Ukraine have free access to public psychiatric assistance, including reimbursement of pharmacological treatment on the same terms as Polish citizens. According to the UHNR data over 4 million displaced people, refugees, came to Poland so far and some of them benefited from such help.Displaced individuals suffer from the consequences of traumatic events, exhibit psychological problems or develop mental disorders, including post-traumatic stress disorder, depressive and anxiety disorders or relapses of psychotic episodes.The lecture will present data from the Interdisciplinary War in Ukraine Research Laboratory by pointing out the most important problems faced by Ukrainian refugees in Poland, why they chose Poland when escaping the war, how they evaluate Polish help, what their integration in Poland looks like. The survey also measured the level of war trauma (RHS-15). The results of the analysis show that most refugees present post-traumatic stress disorder symptoms (76 %), while only 0.15% of this population was treated in public psychiatric facilities.Mental healthcare services are suddenly faced with major challenges and need to develop or expand strategies to address them. The Polish Ministry of Health prepared and started implementation of a reform of the mental health care system for adult as well as children and adolescent psychiatry. This fundamental reform should comprise three main actions, i.e. integration of mental health services into primary healthcare; establishment of community psychiatric services together with the provision of inpatient services in general hospitals; and limitation of the role of mental hospitals to specific tasks only .None Declared


Short-term mechanical circulatory support (ST-MCS) devices have been traditionally deployed in patients with cardiogenic shock, advanced heart failure, cardiovascular collapse, and cardiorespiratory failure. Limitations of the mechanical support devices are typically related to mobility of the patient since the access is frequently through femoral vasculature. This limits the time the patient can be supported by mechanical circulatory support (MCS). We describe deployment of ST-MCS using alternate access such as the subclavian/axillary artery that facilitates ambulation of the patient. These include the deployment of intra-aortic balloon pump (IABP) through the subclavian artery, Impella pump through the axillary/subclavian artery, and extracorporeal membrane oxygenation (ECMO) using the subclavian artery and jugular vein. The field of mechanical circulatory support (MCS) has been evolving steadily as the burden of patients with cardiovascular diseases causing heart failure (HF) has continued to rise exponentially. MCS devices are broadly of two types: short-term and long-term. The short-term devices are used in the setting of cardiogenic shock following acute myocardial infarction (MI), acute massive pulmonary embolism, post cardiotomy patients with failure to wean from cardiopulmonary bypass (CPB), cardiac arrest, myocarditis, cardiomyopathy with acute decompensation, and cardiorespiratory failure . Long-teThe number of patients who are becoming eligible for MCS is rising due to many ongoing technical advances. One of the important factors includes miniaturization of the devices which can be implanted, allowing the patients to stay ambulatory. Ambulatory devices facilitate patients’ recovery by facilitating their ability to undergo physical conditioning. This is crucial for maintaining muscle mass and allows them to recover well or undergo a major procedure like a heart transplant.The evolution from older pulsatile devices to continuous-flow left ventricular assist devices (LVAD) and the incorporation of smaller pumps, with no valves, fewer moving parts, and improved hemocompatibility have translated into improved clinical outcomes, greater durability, fewer adverse events, and reduced overall cost of care. This review aims to provide a summary of the current use of short-term and durable MCS devices in the treatment of advanced-stage HF, highlighting several aspects of LVAD support and the challenges that remain. The intra-aortic balloon pump (IABP) has been the most commonly used temporary mechanical support device over the past 50 years . The useThe subclavian/axillary artery is easily approached in the infra-clavicular region by splitting the pectoralis major muscle fibers and dividing the clavipectoral fascia. The subclavian vein is dissected out and moved downwards, to expose the subclavian artery just as it becomes the axillary artery. This first gained prominence in providing arterial inflow and antegrade cerebral perfusion in aortic surgery. This was adapted to use for implantation of IABPs through the right subclavian artery . This alComponents of the operative procedure are shown in Fig. IABP support has been the most commonly used type of temporary MCS. The device is traditionally used in stabilizing the patients with cardiogenic shock usually in the setting of acute myocardial infarction (AMI), patients with unstable angina, management of mechanical complications of MI, and post cardiotomy patients needing hemodynamic support to wean off CPB. The IABP catheter is usually inserted via a transfemoral approach percutaneously. The device works on the principle of diastolic augmentation, improving coronary perfusion and reduction in systemic vascular resistance due to sudden balloon deflation during systole, causing offloading of the left ventricle (LV). The IABP has been used in the management of HF patients as bridge to recovery, bridge to longer-term LVADs, and as bridge to transplant. Nishida et al. used the trans-axillary approach for IABP placement in 133 patients as bridge to transplant; 70.7% had a graft sutured to the axillary/subclavian artery while the rest of the patients had implants through a percutaneous approach . The groHowever, the main issue with IABP is that it still requires the use of a large external console that will keep the patient hospitalized. The incidence of migration, driveline kinking, and IABP malfunction has been higher when it has been placed via trans-axillary approach . Stroke The open technique involves exposure of the junction of the right or left axillary/subclavian artery junction via a small infraclavicular incision. A 4–7-mm polytetrafluoroethylene (PTFE) graft is sutured to the axillary/subclavian artery and the one-way valve part of the 8-Fr sheath is tied to the graft. The guidewire is introduced through the sheath. Fluoroscopic guidance is used for ensuring the placement of guidewire in the descending thoracic aorta , 6. SeveSupraclavicular access to IABP placement uses ultrasound guidance to access the subclavian artery and then fluoroscopic assistance is used to help position the tip of IABP in the desired position with full length of the sheath retained. The tip of the sheath is placed in the descending thoracic aorta and could potentially prevent the migration of the device. The left subclavian arterial access is preferred with this approach, as the course of the device is straight from the left side and also reduces the chances of cerebrovascular accident (CVA) .Ambulatory veno-venous ECMO using internal jugular venous cannulation has been used more frequently in patients awaiting lung transplantation. Veno-arterial (VA)-ECMO support using alternate access such as the subclavian artery and the subclavian vein or jugular vein is being used in select centers . As cannThe technique of graft sutured to the axillary artery, tunneled subcutaneously allowing chest closure post cardiotomy, has been utilized in ECMO support. This strategy not only provides the advantage of mechanical stability of the chest wall to allow early extubation but also provides all the advantages of ambulatory MCS Table .Table 1AImpella is a micro-axial LVAD over a pigtail catheter which is placed into the LV across the aortic valve. The pump provides circulatory support by ejecting the blood from LV into the aorta, thus unloading the ventricle and allowing reduction of LV wall tension. This device provides circulatory support in patients with cardiogenic shock and allows support prior to definitive therapy and as bridge to recovery. Using trans-subclavian approach allows patient improved recovery as they can actively participate in physiotherapy and ambulation. While the 5.0 and 5.5 versions purport to provide 5 and 5.5 L per minute of flow, this is based on algorithms and do not accurately represent actual flows achieved. Furthermore, at high speeds and sometimes with minor changes in device position, there may be higher rates of hemolysis.This was used first by Raman et al. in the University of Chicago in 2010 (unpublished communication) (figure of graft sutured to the subclavian artery) and then adapted to more widespread use  as experUsually, a right infraclavicular approach is utilized and a 10-mm Dacron graft is sewn as a chimney to the axillary/subclavian artery . The graThe intravascular ventricular assist system (iVAS)  is a minimally invasive, ambulatory, counterpulsation device which can provide long-term support for patients with advanced HF and can potentially provide support while avoiding the need for a standard VAD. The external driver is a pneumatically driven electromechanical pump. The arterial interface and skin interface devices connect the external and internal drivelines. The authors reported their experience in 13 patients with all patients undergoing cardiac transplant at a mean duration of 32 days . An updaManagement of advanced HF can be challenging. Patients often need hospital-based treatment for titration and monitoring of medical therapy. ST-MCS plays an important role in a subset of these patients who need circulatory support to reverse the cardiac dysfunction and define management pathway in patients who do not improve. Several devices have been available to facilitate patient management. The concept of ambulatory MCS has become popular in the last decade or so. These techniques provide better patient management in the hospital environment allowing more independence to patients who are likely to become malnourished and deconditioned with HF.Choice of the device depends on the operator and/or institutional experience. None of the systems available is without their own problems. This is an ongoing area of development and future work needs to focus not only on refining the technology but also define the management pathways to tailor a system to the requirement. There is a need to develop reliable devices which may allow the patients to undergo their recuperation in the community.


We describe the trapping and absorption of audible sound in centimeter-scale claddings of two-dimensional, locally resonant phononic crystals. In a square lattice of local resonators consisting of steel cores and cellulose shells, embedded in a viscous foam, dual acoustic-range band gaps extending from about 200 to  The advent of locally resonant acoustic metamaterials has been a vital first step in controlling sound with wavelength scales of meters in air, using centimeter-scale resonators6. Rapid and accurate fabrication of phononic crystals through recent advances in additive manufacturing has provided the next step forward12. Phononic crystals, consisting of three-dimensional lattices of centimeter-sized local resonators, can exhibit dual phononic band gaps, extending over a frequency range from 200 to 14. Here, dual phononic band gaps, consisting of separate local resonance and Bragg gaps, can block the transmission of sound through wave-interference effects. The formation of these phononic band gaps may require only a few unit cells in thickness of the periodic structure. When embedded in a realistic viscoelastic foam background, the avenues for sound sculpting involve a combination of local resonance and wave interference. In this article, we present numerical simulation of sound trapping and waveguiding in thin slabs of two-dimensional, locally resonant phononic crystals, toward the goal of audible sound sculpting.The frequency-selective sculpting of audible sound with centimeter-scale cladding material is an endeavor of considerable potential significance15. Local resonators typically consist of a dense and stiff core coupled to a stiff shell via a layer of soft interstitial foam. Locally resonant phononic crystals, consisting of an acoustically connected array of such local resonators, typically exhibit two disjoint band gaps, namely a local resonance gap and a Bragg gap. The local resonance gap occurs when the effective mass and moment of inertia of the local resonators are simultaneously negative17. On the other hand, the Bragg gap arises from the macroscopic, destructive interference of waves scattered from the lattice.In this paper, we model realistic, open-cell, acoustic foam as a viscoelastic material using the fractional Voigt modelWe illustrate, in two-dimensional examples, that frequency-selective cavity and waveguide modes can be created, respectively, by a point and a line defect in the otherwise periodic lattice. By replacing a local resonator in the lattice by a non-resonant shell, cavity modes which are associated with the translation and rotation of the defect shell are created exclusively in the local resonance gap. On the other hand, the removal of a resonator and subsequent replacement by the background material produce cavity modes exclusively in the Bragg gap.By replacing a line of local resonators by non-resonant shells, waveguide modes permeate the original local resonance gap, and wave propagation is localized along the line defect via the in-plane translations and rotations of the non-resonant shells. When a line of resonators is removed from the lattice, the local resonance gap remains unaffected. Instead, waveguide modes fill the higher frequency Bragg gap. We show that the frequency spectrum of these waveguides can be controlled by choosing the width of the line defect. By removing a line of the resonators and then reducing the vacant space of foam, a smaller number of waveguide modes can be created and their frequency range can be reduced. By removing a line of resonators and then inserting a solid cellulose rod along the line, we demonstrate that waveguide modes can be engineered simultaneously in both local resonance and Bragg gaps. In a thin cladding of such a phononic crystal, it may be possible to almost completely contain and absorb sound from a noisy source over a broad audible range. By a suitable choice of frequency-selective, waveguide sound outlets that traverse the cladding, it may be possible to sculpt sound almost at will and release a low-intensity, euphonious, version of the sound to the surrounding environment.18:At a given position 19:The energy loss in a damped harmonic oscillator arises from a frictional force that is proportional to the magnitude and opposite in direction to the velocity of the oscillator. Similarly, viscoelasticity in a linear continuum is described by a damping term of the stress that is proportional to the rate of strainIn oscillatory systems, it is customary to represent viscoelasticity by complex-valued, effective elastic moduli. At a driving frequency entclass1pt{minima15. The strain K produces a stress 21, and is experimentally shown to accurately characterize soft materials23. For simplicity, we employ the simple fractional Voigt model in this article. More realistic models, such as the fractional Zener model, generally require more springs and generalized dashpots of different power exponents25.The fractional Voigt model for viscoelastic material, depicted in the insert of Fig. 26. In this paper, we consider only the weakly damped regime as depicted in Fig. 26.For a weakly damped foam, we choose mentclass2pt{minimmentclass2pt{minimPhononic band gaps are observed in locally resonant phononic crystals. The absence of wave modes in a phononic band gap implies that wave propagation is evanescent. The band gaps can be broadly classified into local resonance gaps and Bragg gaps. Local resonance gaps occur over the frequency range where the effective masses and moments of inertia of the acoustically connected local resonators are simultaneously negative. The frequency range of local resonance gaps is insensitive to lattice arrangements, provided that the resonators remain acoustically connected. Bragg gaps are caused by the macroscopic resonances of the array of local resonators, and sensitively depend on the lattice configuration. Frequency-sensitive waveguide modes can be engineered in a desired spectral range, by line defects of local resonance and crystal periodicity.27 (28). The unit cell is depicted in Fig. The supercell method is employed to study point-defect cavity modes and line-defect waveguide modes in periodic systems. In the present work, we study cavity modes and one-dimensional waveguides in two-dimensional locally resonant phononic crystals. Cylindrically symmetric core-shell resonators are arranged in a square lattice with a lattice constant entclass1pt{minimaWith a small power exponent, the effective elastic moduli are fairly insensitive to frequency at frequencies above 29, where a generalized dispersion The actual band structure with frequency-dependent elastic moduli can be calculated by the Cutting Surface MethodThe in-plane bands of the The finite-element method (FEM) is employed to simulate the reflection, transmission and absorption across a finite-thickness locally resonant phononic crystal. The two-dimensional system is assumed to be infinite in the out-of-plane direction, and repeating in the lateral direction. We consider a cladding that is 3 unit cells thick. The phononic crystal cladding unit cell is chosen to be a The transmission, reflection and absorption coefficients across the 3-cm layer of locally resonant acoustic phononic crystal are plotted in Fig. 31. When a resonator is replaced by the background material, cavity modes are created exclusively in the Bragg gap of the original structure. In contrast, removal and subsequent replacement of a resonator by a defect shell creates cavity modes exclusively in the local resonance gap. In the following, we delineate the two types of cavity modes and illustrate their interactions with an incident pressure wave in FEM simulations.The elastic displacement field is evanescent in the band gap of the phononic crystal. Point defects in the otherwise periodic lattice create spatially localized cavity modes, and enable frequency-selective coupling of sound into the band gaps of the original phononic crystalCavity modes are introduced in the Bragg gap by the removal of a resonator in the otherwise perfect lattice. We refer to this kind of positional disorder as a Bragg point defect. The transmission spectrum across such a locally resonant phononic crystal cladding, of 3 unit cells in thickness, is plotted in Fig. Cavity modes are introduced exclusively in the local resonance gap by the replacement of a core-shell resonator by a defect shell. In this case, the steel core of the resonator is replaced by foam. It is referred to as a local resonance point defect. The transmission spectrum across a 3-cm locally resonant phononic crystal slab with a local resonance point defect is plotted in Fig. 37. Different waveguide designs facilitate sound transmission through parts of the local resonance gap, through parts of the Bragg gap, or both gaps. These involve removal and replacement of local resonators along lines connecting the interior and exterior of the phononic crystal cladding. In the following, we describe the properties of the different types of waveguide modes in viscoelastic, locally resonant, phononic crystal slabs. We also numerically simulate their interactions with an incident pressure wave.Wave propagation is evanescent within the band gaps of a phononic crystal. Frequency-selective transmission of sound can be enabled by engineering specific waveguide channels that allow passage of sound through the otherwise impenetrable phononic band gapsWaveguide modes are introduced in the Bragg gap by the removal of a line of resonators and re-adjustments of the distance between the phononic crystals on either side of the vacancy. We denote by The in-plane bands of a supercell with 8 remaining local resonators and a line defect of width The waveguide mode elastic displacement fields, for The transmission, reflection and absorption coefficients across the 3-cm cladding with a line defect The coupling between the incident pressure wave and the phononic crystal cladding is restricted by symmetry requirements and boundary conditions. By reflectional symmetry, the pressure wave at normal incidence can excite the longitudinal waveguide modes, but not the transverse and rotational modes. Moreover, shear and compressional waves propagate at different speeds of sound, and are generally decoupled in linear, isotropic solids. The compressional pressure wave in air does not couple to the transverse and rotational shear waves in the elastic or viscoelastic solids.Waveguide modes are introduced exclusively in the local resonance gap by a line defect where the local resonators are replaced by non-resonant shells. The supercell band structure with 8 local resonators and a line defect of non-resonant shells is plotted in Fig. The transmission, reflection and absorption coefficients across the 3-cm layer of locally resonant phononic crystal are plotted in Fig. a, is made of the same material as the shell of the resonator. Compared to the supercell band structure of the base structure in Fig. Waveguide modes extend throughout both the local resonance gap and the Bragg gap by the removal of a line of resonators and concomitant addition of a rigid cellulose rod in the waveguide foam. The supercell band structure with 8 local resonators and a line defect with a rigid rod waveguide is plotted in Fig. The displacement fields of these relevant waveguide modes are plotted in Fig. The transmission, reflection and absorption coefficients across the 3-cm layer of locally resonant phononic crystal are plotted in Fig. 38 may function quite effectively within locally resonant phononic crystal claddings to selectively allow more transmission of desired sound frequencies.In the above illustrations, overall transmission levels remain quite low due to our use of a relatively lossy background foam. A less lossy, environmentally friendly, natural fiber-reinforced compositesIn summary, we have illustrated the sound trapping and waveguiding properties of various locally resonant phononic crystals. This reveals remarkably broadband control of reflection, transmission and absorption of audible sound in phononic crystal claddings of only a few unit cells in thickness. This is facilitated by the dual band gap nature of the underlying locally resonant medium. Our work reveals important design principles in the construction of acoustic claddings for the mitigation of unwanted noise and the spectral sculpting of sound for the surrounding environment.Locally resonant phononic crystals exhibit a local resonance gap and a distinct Bragg gap. The former occurs when the effective mass and effective moment of inertia are simultaneously negative and relies on the anti-phase oscillations of acoustically connected resonators. The latter, resulting from the macroscopic resonances of a periodic collection of resonators, scales with the lattice spacing. Spatially localized cavity modes are created in the local resonance gap by replacing a core-shell resonator by a defect shell. Likewise, waveguides in the local resonance gap can be engineered by replacing a line of local resonators by non-resonant shells. The resulting cavity and waveguide modes involve longitudinal, transverse and rotational oscillations of the non-resonant shells. On the other hand, cavity modes appear in the Bragg gap when a core-shell resonator is replaced by the background foam. The frequency extent of the waveguide modes can be controlled by the width of the positional line defect. For a narrow waveguide with The acoustic response to an incident pressure wave of the locally resonant phononic crystal that we have considered is predominated by the translational and rotational oscillations of the rigid components. However, the rotational degrees of freedom do not couple effectively when the pressure wave is normally incident. Defects in the phononic crystal lift the discrete translational symmetry of the lattice, enabling richer and more diverse acoustic responses.Reflection symmetry can be lifted through oblique incidence of the pressure wave. The FEM simulations with the various phononic crystal slabs were repeated at oblique angles of incidence. While the resultant transmission and reflection spectra show small frequency shifts of the transmission peaks, excitations of the rotational modes are insignificant. A plausible explanation is the stark contrast in the speed of sound between air and the phononic crystal constituents. The speed of sound in air is 39. Future work may focus on numerically stable and accurate implementation of time-domain simulations for elastic and viscoelastic composites involving large contrasts in material parameters. One possibility is to model resonators as rigid bodies with frequency-dependent, effective masses and moments of inertia17. Another possibility is employing an adaptive mesh, which is denser in foam with low speeds of sound, and coarse in stiff solids with high speeds of sound. Nevertheless, the mesh in the regions of the stiff solids cannot be too coarse to faithfully represent their geometries.In our present work, all numerical simulations are performed in the frequency domain. In principle, considerable computational resources can be saved using time-domain methods. When the finite-thickness structure is excited by a Gaussian wave pulse with a finite spectral width, a broad frequency range of acoustic response can be simulated simultaneously in one trial. The reflection and transmission coefficients over the desired spectral range can be calculated by numerically efficient fast Fourier transform (FFT) of the reflected and transmitted pulses respectively. However, the conventional implementation of finite-difference time-domain (FDTD) method is problematic for structures containing materials with large density contrasts41. Biodegradable “green” materials with less sound absorption are advocated to replace non-recyclable melamine and polyurethane for acoustic panels. These may enable enhanced sound transmission at higher audible frequencies.Future analysis would benefit from more realistic models of environmentally friendly viscoelastic materials. For simplicity, we assumed a simple isotropic fractional Voigt model with identical loss factors for compressional and shear deformations. More realistic models of viscoelastic materials may involve multiple dashpots of different power exponents and characteristic times. The actual loss factors for shear and volumetric deformations may differ, depending on the relative motion between the air in foam and the elastic skeleton14. The design of waveguide channels in a three-dimensional phononic crystal cladding may provide unprecedented, real-world, opportunities for audible sound control at will.An important generalization of our analysis is three-dimensional viscoelastic phononic crystals. It is anticipated that three-dimensional, locally resonant phononic crystals may exhibit an even broader bandwidth of audible sound control. For example, a body-centered cubic crystal of local resonators exhibits dual audible-range band gaps over a frequency range from 600 to


This study presents a case report of an inflammatory dentigerous cyst of tooth #35, associated with its previously endodontically treated deciduous predecessor. Cystic lesion growth caused impaction of the second premolar, displacing it closer to the lower border of the mandible. The lesion represents a typical dentigerous cyst that possibly arises in association with periapical inflammation of a deciduous molar involving the follicle of the premolars. This report highlights the inflammatory etiology of dentigerous cysts, which mainly occur in mixed dentition. A 12-year-old patient was referred to Oral Surgery Department regarding a sizeable radiolucent lesion in the unerupted mandibular second premolar region, detected on an Orthopantomagram (OPG) X-ray. A non-vital primary predecessor had been endodontically treated at least one year before an examination, with a control OPG X-ray showing no signs of pathology at the time. The patient did not report any symptoms. Clinical examination revealed an egg-like tumefaction of the alveolar bone in the left premolar region of the mandible. Cone-beam computed tomography analysis showed a sizeable translucent lesion surrounding the crown of the impacted tooth. The lesion was enucleated in its entirety, along with the impacted premolar, under local anesthesia. Clinical findings combined with radiographic and microscopic examinations confirmed the diagnosis of an inflammatory dentigerous cyst. The seventeen month follow-up revealed good bone healing. This case presented a rare complication of endodontic treatment of deciduous teeth and informed on possible complications of endodontic therapy in deciduous teeth, emphasizing the importance of early diagnosis of cysts in preventing extraction of permanent teeth. Odontogenic cysts are described as a heterogeneous group of cystic lesions of the mouth, originating from the tissue of the dental organ. They are the second most common cystic lesion of the jaws, radicular cysts being the most prevalent ones. All odontogenic cysts combined comprise up to 24% of all true cysts of the jaws, making them the most common type of oral cyst to be found in children . Being cThe exact etiopathogenesis of these cysts still remains unclear , 5. BennThey frequently arise in mixed dentition, during the first years of the second decade, more often in boys than in girls . They arThis case report shows a clinical finding of a dentigerous cyst of a tooth, related to its previously endodontically treated primary predecessor. The aim of this report is to point out this possible negative outcome of endodontic treatment in primary teeth, potentially leading to the loss of permanent teeth. It is important to highlight the importance of periodic control examinations of endodontically treated primary teeth, with the goal to prevent such negative outcomes.The patient, a twelve-year-old girl, was referred to the Clinic of Oral Surgery by her orthodontist, due to a suspected cystic lesion in the mandible routinely discovered on the Orthopantomagram (OPG) X-ray. The patient had previously denied having any subjective symptoms. Clinical examination revealed a significant swelling in the vestibule of the left premolar mandible region between teeth #34 and #36. These findings indicated the presence of a relatively big cystic lesion. There was no visible extraoral deformity, which is why neither the patient's parents nor the patient herself noticed anything unusual.Analysis of the OPG X-ray showed a round radiolucency in the left premolar region of the mandible . The cysIt is worth pointing out that an OPG X-ray was made two years prior to this diagnosis, and had shown no signs of pathology, with normal and expected position of both teeth, the primary second molar, and its secondary successor .Following the administration of the local anesthetic, two vertical incisions were made in the region of teeth #33 and #36. A trapezoid mucoperiosteal flap was carefully raised. Upon direct inspection, the vestibular bone was found to have a round, ball-like deformity. After the deciduous molar was extracted, the bur was utilized to remove the thinnest part of the vestibular bone. A clear, yellow cystic fluid was aspirated. The surgical protocol contained total enucleation of the cyst, including the impacted permanent second premolar. After the wound irrigation was done, the mucoperiosteal flap was advanced, and two apical mattress sutures were placed. A complete cystic lining containing a permanent tooth was then sent for histopathological examination .Postoperative medications included analgesics and antibiotics. The patient did not report any significant pain or complications during recovery. Due to a sizeable bone defect caused by the expansive growth of the cyst, orthodontic therapy was postponed until proper bone healing. In summary, the plan was to place a space maintainer to save room for a future implant.Microscopic analysis of the sample material confirmed the diagnosis of a dentigerous cyst. It was also noted that the fibrous cystic wall contained an infiltrate with a large number of chronic inflammatory cells. The epithelium of the luminal surface of the fibrous cystic shell was classified as hyperplastic squamous epithelium without keratinization .A control examination was made one year after the surgery. The patient did not report any symptoms. Clinical and radiologic examination showed good bone healing, with no signs of relapse .Dentigerous cysts originate from the tissue of tooth follicles and are the most commonly diagnosed ones among all cysts of developmental origin . They arThere are a few theories explaining the origin of dentigerous cysts. Even though their precise etiopathogenesis still remains unclear, they are mainly thought to be of developmental origin , 2. It iBloch-Jorgensen was the first to propose inflammation as a potential trigger of dentigerous cyst formation. A series of case reports published by Bloch-Jorgensen showed the relationship between dentigerous cysts in primary teeth with their carious and necrotic primary predecessors . AccordiAzaz and Sheyter published a mini-series of five cases of dentigerous cysts forming around the mandibular second premolar, with apices of necrotic deciduous teeth in their close proximity . They suBased on these clinical reports, authors Benn and Altini proposed categorizing dentigerous cysts into two groups based on their origin: developmental and inflammatory dentigerous cysts . AccordiDentigerous cysts of inflammatory origin usually occur in the mandible, with the mandibular second premolars being the most frequently affected teeth of the jaw , 15. AccThis case report discusses the diagnosis of a dentigerous cyst in a child patient during the mixed dentition period. The affected tooth in this case, the mandibular second premolar, as well as the distinct microscopic finding of an abundant chronic inflammatory cell infiltrate in the fibrous capsule of the cyst, supports the theory of the inflammatory origin of these cysts, first proposed by authors Benn and Altini . RadiogrThe infection, as a possible etiological factor of the cyst, in our case could originate as a consequence of the residual necrotic pulp tissue from the root canal of a previously pulpotomy-treated deciduous second molar. Pulpotomy was not performed at our clinic, and we were unable to obtain information on where and with what material (method) the pulpotomy was conducted.Devitalization pulpotomy in two stages is still the most commonly used technique in our region for the treatment of pulp chronic infections in primary teeth. In the first session, devitalization paste based on paraformaldehyde is applied on the coronal pulp exposure, and in the second session after coronal pulp removal, antiseptic (zinc oxide eugenol paste and iodoform paste) or mummifying paste (based on parachlorophenol and camphor) is applied to the canal entrances. We cannot rule out the possibility that some of the materials used for the pulpotomy were the trigger for the cyst formation . Other vFaugeron et al. and Petel et al. found no evidence to identify one superior pulpotomy medicament and technique clearly among ferric sulphate, formocresol, and MTA method , 21. ThePulpectomy and lesion sterilization/tissue repair are appropriate methods for non-vital pulp treatment for primary teeth diagnosed with irreversible pulpitis or necrotic pulp .Keeping the preceding in mind, it is also important to highlight the necessity of maintaining appropriate medical records and having them readily available because we cannot be certain that the cyst emergence was not caused by the irritating effect of some of the materials used. In order to detect possible complications on time, we emphasize the importance of continuous clinical and radiographic monitoring of all endodontically treated primary teeth.There are a couple of different treatment approaches for dentigerous cysts proposed in the literature . ConservBased on clinical and radiological findings, the prognosis of a spontaneous eruption of the impacted tooth in this case was very poor, due to its severe dislocation and angulation in the bone. Therefore, the dentigerous cyst was totally enucleated, including the impacted second premolar. Control checkup after seventeen months showed no signs of recurrence, with good bone healing.The aim of this report was to highlight a potential complication of endodontic treatment of deciduous teeth, which can lead to the loss of permanent teeth. Improper endodontic treatment of the primary tooth indicates tooth extraction, with recommended periodic follow-up until an eruption of its permanent successor is finished. Therefore, it is of utmost importance to timely spot any changes in the expected eruption of primary teeth. The prolonged presence of primary teeth with no signs of root resorption should be evaluated by radiologic examination. Parents should be made aware of this potential complication of primary tooth endodontic treatment in order to recognize obvious signs and symptoms indicating the formation of cystic lesions in children.


Characteristics in healthy aging were not shown to differ. These results indicate that activity in MCI exhibits cross-frequency network reorganization characterized by increased heterogeneity of node roles in the functional hierarchy. Aging itself is not found to cause VSTM functional hierarchy differences.Alzheimer's Disease (AD) shows both complex alterations of functional dependencies between brain regions and a decreased ability to perform Visual Short-Term Memory Binding (VSTMB) tasks. Recent advances in network neuroscience toward understanding the complexity of hierarchical brain function here enables us to establish a link between these two phenomena. Here, we study data on two types of dementia at Mild Cognitive Impairment (MCI) stage—familial AD patients (E280A mutation of the presenilin-1 gene) and elderly MCI patients at high risk of sporadic AD, both with age-matched controls. We analyzed Electroencephalogram (EEG) signals recorded during the performance of Visual Short-Term Memory (VSTM) tasks by these participants. Functional connectivity was computed using the phase-lag index in Alpha and Beta; and network analysis was employed using network indices of hierarchical spread (degree variance) and complexity. Hierarchical characteristics of EEG functional connectivity networks revealed abnormal patterns in familial MCI VSTMB function and sporadic MCI VSTMB function. The middle-aged familial MCI binding network displayed a larger degree variance in lower Beta compared to healthy controls ( Functional disconnections caused by Alzheimer's disease (AD) can be characterized using brain network methodologies of patients and those at risk of this type of dementia   Those embarked on the course of familial and sporadic variants of AD will exhibit notable deviations in their VSTMB functions, (2) that such deviations will be accounted for by changes in network topology which would be similar across variants of risk of AD, and (3) VSTMB functional dependencies will not exhibit age-related changes.The data in this study have been used in two previous studies  and 10 healthy controls  from Antioquia, Colombia. Each patient carried the mutation E280A of the presenilin-1 gene which leads to familial AD in 100% of carriers. The data consist of sixty-channel EEG activity recorded with a 64 channel EEG cap using SynAmps 2.5 in Neuroscan at 500 Hz and bandpass filtered from 1 to 100 Hz with impedances below 10 KΩ. Four ocular channels were discarded after being used to factor out oculomotor artifacts. The patients had not yet developed clinical symptoms warranting a diagnosis of dementia. Analysis of power-frequency spectrum showed that this data had been subject to a low pass filter with cut-off at 20 Hz.The sporadic MCI data consisted of 13 patients diagnosed with MCI  and 19 healthy controls  recruited from the Institute of Cognitive Neurology (INECO), Buenos Aires, Argentina. Criteria implemented for diagnosis derived from Petersen  and WinbFor both datasets we use data from the encoding period during the performance of shape only and shape-color binding tests since deficits at this stage seem to be responsible for the VSTM binding problems found in AD  is singled out by contrasting tasks for the recognition of colored shapes, which requires binding of shape and color in memory retention (binding), and the recognition of single shapes which only requires the retention of constituent features. In the change detection task assessment of VSTM for shape alone, the arrays consist of three different black shapes and in the binding task the arrays consist of three different shapes each with a different color. Each task trial consists of an encoding period (500 ms), during which a study array is displayed on screen, followed by an unfilled short delay (900 ms) and test period with a test array. During the test period, participants are prompted to respond whether or not the objects in the two arrays are identical. The positions of the objects are randomized between arrays to avoid use of location as a memory cue. Both shapes and colors are chosen randomly for each trial from a set of eight shapes and a set of eight colors. A randomly chosen fifty percent of the trials have the same objects in both arrays. In the other 50 percent, two shapes seen during the encoding periods are replaced with two new shapes selected from the set, whereas in the binding task two colored shapes of the test display swap the colors they had during the encoding period. All participants start with a brief practice session before undergoing one hundred trials per task. Binding and shape tasks are delivered in a counterbalanced order across participants. Z = 1.54 and their Controls Z = 1.42; MCI-FAD Z = 1.63 and their controls Z = 1.17; see Pietto et al., Z = −0.09, p = 0.93, d = 0.02; see Pietto et al., Both groups showed similar level of performance across task conditions i.e., Shape Only vs. Shape-Color Binding (MCI The Phase-Lag Index (PLI) was computed to assess the phase-dependent functional connectivity of the EEG channels . This threshold is based on the clustering coefficient, fixing the network at the balance point of integrative and segregative properties  could be understood physiologically as the level of network operational organization.Physiologically, this measure could then inform about the expansion and/or strengthening of network structures and hierarchies. Complexity on the other hand, arises from the structure of the interactions between units   in both datasets. Differences were computed between binding and shape values for patients and controls separately. These values were then compared between patients and controls using Wilcoxon rank sum tests. V in Beta1 for the familial MCI data. In 9 of the 10 patients, the degree variance of the binding condition is larger than in the shape condition, R in Alpha with an effect size of 1.0124, which was not replicated in familial MCI and control. In 12 of the 13 patients, the hierarchical complexity of the binding condition was larger than in the shape condition, We computed p-values were roughly of the same magnitudes as in the individual dataset differences found, although the effect sizes were comparatively reduced.Both the greater degree variance in MCI in Beta1 and greater hierarchical complexity in MCI in Alpha held as effects when combining the datasets. The V and R are based on variances of degrees which can be expected to be higher for larger network sizes. Thus, to assess healthy aging of VSTM binding we downsampled the sporadic 128-channel dataset to the same size (sixty) as the familial dataset. These datasets use different layout systems for electrodes, but approximate mapping between these layouts is known  seemingly accounting for VSTM binding deficits. These results fit well the current understanding of network reorganization in carriers of AD mutation  prior to the dementia onset. For example, using a measure of information sharing , Parra et al. . Hierarchical complexity is a new paradigm for brain networks which has previously been explored in EEG signals and structural MRI from healthy participants . ERP data involving patients at risk of AD due to different disease variants and with very different ages indicated that neither of these factors modified the effect that AD exerted on VSTMB, thus suggesting that its decline can be more reliably linked to the AD pathology  while in older brains experiencing MCI with unknown genetic factors, it hampers their hierarchical complexity. We can speculate that the latter indicates the additive effect of aging on AD pathology. Homeostatically, younger brains are better equipped to cope with pathology and to reorganize functional networks. AD impacting on older brains may encountered a less favorable biological scenario. Such a scenario has already witnessed compensatory changes  to normal aging Grady, . It is aWe studied the functional connectivity computed from EEG during the VSTMB task in MCI stage familial AD patients and elderly MCI patients at high risk of sporadic AD as well as respective populations of age- and education-matched healthy controls. While no network differences in VSTM tasks were found due to healthy aging nor between elderly and middle-age onset MCI, clear differences in hierarchical characteristics of functional network degrees between binding and shape tasks were found in MCI but not healthy control in both datasets. It was revealed that the difference in degree variance of EEG networks in the familial AD dataset in lower Beta was significantly larger in patients with no difference found in hierarchical complexity. In conjunction, the difference of hierarchical complexity of EEG networks in the sporadic AD dataset in Alpha was significantly larger in patients with no difference found in degree variance. Combining datasets supported both increase in degree variance in lower Beta and increase in hierarchical complexity in Alpha as general characteristics of AD functional connectivity in binding. The increased complexity in elderly patients in the binding task suggests cross-frequency compensatory coupling mechanisms in an attempt to overcome the pathological damage of this disease, illuminating the possibility of a double-sided compensatory effect targeted at joint age-related and pathological decline in the brain.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics Committees of the University of Antioquia and INECO. The patients/participants provided their written informed consent to participate in this study.KS conducted the data analyses, wrote the manuscript, did the literature search, and produced the figures. JS contributed to the study design and writing. JE contributed to the study design and data analyses and revised the text. AI was involved in collecting and providing the data and revised the text. MP designed the study, interpreted the findings, and contributed to the writing. All authors contributed to the article and approved the submitted version.KS reports grants and personal fees from Engineering and Physical Sciences Research Council, and grants from Medical Research Council during the conduct of the study; AI reports grants from Takeda CW2680521; CONICET; FONCYT-PICT ; ANID/FONDECYT Regular ; ANID/FONDAP (15150012); ANID/PIA/ANILLOS ACT210096; and the Multi-partner Consortium to expand Dementia Research in Latin America (ReDLat), funded by the National Institutes of Aging of the National Institutes of Health under award number R01AG057234, an Alzheimer's Association Grant (SG-20-725707-ReDLat), the Rainwater Foundation, and the Global Brain Health Institute. MP work was supported by Alzheimer's Society grants AS-R42303 and AS-SF-14-008.The content is solely the responsibility of the authors and does not represent the official views of these institutions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The application of three-dimensional printing technology in the medical field has great potential for bone defect repair, especially personalized and biological repair. As a green manufacturing process that does not involve liquefication through heating, low-temperature deposition manufacturing (LDM) is a promising type of rapid prototyping manufacturing and has been widely used to fabricate scaffolds in bone tissue engineering. The scaffolds fabricated by LDM have a multi-scale controllable pore structure and interconnected micropores, which are beneficial for the repair of bone defects. At the same time, different types of cells or bioactive factor can be integrated into three-dimensional structural scaffolds through LDM. Herein, we introduced LDM technology and summarize its applications in bone tissue engineering. We divide the scaffolds into four categories according to the skeleton materials and discuss the performance and limitations of the scaffolds. The ideas presented in this review have prospects in the development and application of LDM scaffolds.  Bone defects, mostly those concerning a young and athletic population, are increasingly receiving attention . In geneLDM was firstly reported in 2002 for the fabrication of bone tissue engineering scaffolds, which is based on traditional fabrication technologies such as direct ink writing . The matTypically, the LDM material is fully dissolved in an organic solvent, such as 1,4-dioxane, and the ink is mixed evenly adopting an emulsion stabilizer and ultrasonic technology. Then, the ideal material properties are obtained by adjusting the appropriate mass ratio of the different materials and the mixture is stirred well to form a uniform liquid paste . The conSynthetic materials have better mechanical properties whereas natural materials have better biocompatibility in scaffolds . UnfortuUsually, the structure and pore size of scaffolds determine the cell growth and regeneration of bone tissue. Material properties can be optimized by adjusting the parameters of the LDM system to print more ideal bone tissue engineering scaffolds. The parameters of the LDM system include the proportion of the composite material, the design of the model, the concentration of the material and the working parameters of the devices . AccordiThe shape and architecture of scaffolds depend on the models designed using computer software . CAD tooHydroxyapatite (HA) and other related Ca/P-based bio-ceramics have been used in the manufacturing of bone scaffolds for their varying osteoconductive and osteoinductive properties. They not only exist naturally in bone tissue but also have high mechanical strength and biodegradability. Moreover, the biodegradation rates can be optimized by adjusting the molar ratio of Ca and P in the optimized compound. In addition, the inorganic materials can be categorized into silicate-based glasses, borate-based glasses and phosphate-based glasses according to the components of the bioactive glass . The maj3(PO4)2) to print scaffolds at room temperature and dried the scaffolds for 24 h. The structures were designed on the basis of stereolithography data and modified with 20% DAHP powder to improve the conversion rate and mechanical reinforcement , are naturally degradable and can be used to optimize the ceramic scaffolds. HA and collagen are often added to the precursor solution to improve the mechanical and clinical properties of the scaffolds . The scain vitro showed that PRP composited scaffolds have better bone mineralization and cell proliferation, but the efficacy for bone regeneration in vivo remains controversial. Another disadvantage of ceramic material is the low retention level of growth factors and drugs. Therefore, bioactive substances such as live cells and growth factors are integrated in bioinks to increase the biological activity and osteogenic ability of bone repair materials. It is not a difficult task to impregnate biological factors into the mixed bioink and the low temperature avoid the risk of thermal degradation of drugs or growth factors. To overcome the shortcomings, Lee et al. designed a new composite with stable structure using CDHA, collagen, and plate-rich plasma (PRP) to enable better growth and differentiation of cells . They usCompared with ceramics, polymeric materials have more versatile physicochemical properties that suit clinical applications. Synthetic polymers usually have good processability and mechanical properties and are thus used widely in preparing materials for bone tissue engineering technology . Table 3It is often necessary to composite bioactive factors or modify the materials to increase biocompatibility or osteogenic capacity. PLGA is an excellent biomaterial for bone scaffolds with biodegradability and biocompatibility and has good matrix for pearl powder, which can provide bioactivity for PLGA . Xu et aHydrogels have strong hydrophilicity, that provides an environment suitable for cell proliferation and differentiation. Therefore, the biological activity and mechanical properties of the scaffold can be improved by compositing hydrogel and polymer. For example, a novel composited PLGA-gelatin/chondroitin/hyaluronate scaffold was fabricated to keep the differentiation of mesenchymal stem cells (MSCs) and improved the regeneration of cartilage . Kim et in vivo (Zhao et al. dispersed PLLA containing ibuprofen into sodium alginate aqueous solution to prepare the bioink . The scain vivo  (Gao et in vivo . CompareHigh-molecular-weight polymers usually have poor geometric properties, such as a poor pore size and poor porosity and interconnection, which affect the attachment of scaffolds to cells. Generally, the ability of a polymer to support bone conduction is improved by adding ceramic filler to form a polymer–ceramic composite scaffold. Compared with pure polymer, ceramic composites have obvious benefits in terms of cell performance. in vitro cell experiments showed that cell viability on the surface of the scaffolds was time dependent and unaffected by the composited PLGA/nHA (The fabrication of PLLA/TCP composite scaffolds for bone tissue engineering was first presented by PLGA/nHA .Hydrogels and collagen have been used to increase the hydrophilicity of scaffolds composited with ceramics and polymeric materials. For example, PLGA/β-TCP scaffolds prepared by LDM have been wrapped with collagen to improve the hydrophilicity and osteogenic differentiation . They foAnother major advantage of LDM in biomaterial application is the potential of including drugs and growth factors to improve bone healing or resist infection during the creation of polymer–ceramic composites. 2+ and BMP-2. Another type of diphasic magnetic scaffold was fabricated by LDM with PLGA, collagen, nano-hydroxyapatite, and Fe2O3 using a low-temperature rapid prototyping instrument at −4°C (2 microspheres, on scaffold materials to increase osteogenesis (2 improves the expression of transcription factors by releasing O2 and thus promotes osteogenesis. RGD-containing peptides have the ability for modulation of cell adhesion and differentiation ( at −4°C . It had ogenesis . It is wogenesis . Magnesiogenesis . Scaffologenesis  (Lai et ogenesis . Wang etntiation .−1. 3D-printed scaffolds have been fabricated with gelatin and SF, platelets, or polyols adopting crosslinking and freeze-drying technologies (There are scaffolds that are constructed without compositing a ceramic or polymer framework. nologies . He et aIn this article, we introduced the technical process of LDM and reviewed the applications of this technology to bone tissue engineering scaffolds. As a green manufacturing method, LDM not only controls the pore size of the scaffolds through the use of CAD tools, but also preserves the activity of biological factors. However, there remain many challenges in the LDM of scaffolds. First, the mechanical strength of a scaffold fabricated by LDM is commonly low. Although composited materials improve the mechanical properties, the strength requirements of load-bearing bone are not met. In addition, it is difficult to select a solvent that dissolves both synthetic and natural polymers. Few solvents have been used up to the point and it is undeniable that the benefits of this technology are underutilized. Secondly, it is difficult to balance the degradation of scaffold materials with the regeneration of new bone tissue. There is no doubt that such osteogenesis is not ideal when the degradation rate of scaffolds is faster than the regeneration rate of new bone. Furthermore, the majority of the degradation products are acidic and thus mildly toxic or even toxic to the human body. In addition, a suitable substrate temperature and requirements of the printing platform are not clear. In brief, materials printed on cold plates and freezers form ice crystals in different orientations, which control the microstructures of porous scaffolds. Developing a more suitable low temperature printing system is one of the future research directions.Bone regeneration is not just a simple process of bone formation and resorption. It is a multi-system including the musculoskeletal system and immune system . In addiAn ideal bone tissue engineering scaffold fabricated by LDM has the following properties. The scaffolds must, first and foremost, be of high mechanical quality to suit the demands of bone tissue, particularly the stability required by load-bearing bone. Second, the material should have strong cytocompatibility and a capacity for bone conduction, vascularization, nervousness, and disintegration, among other good biological qualities. Third, the interfacial repair of complicated bone defects depends on the creation of multilayer gradient scaffolds made of bone, cartilage, and soft tissue. LDM is a promising RPM technique that promises the fabrication of ideal scaffolds and is expected to become indispensable in bone tissue engineering. The next step is to investigate various solvent systems for blending different materials or bioactive components and to develop an ideal printing workstation. Bioinks with optimal properties have been prepared by adjusting parameters to obtain a balance of mechanical properties and biological activity in scaffolds. In future work, composite scaffolds with near-ideal levels should be further prepared with LDM technology to promote the regeneration of bone tissue and surrounding tissues and ultimately realize multi-organ bioprinting.


Foreign body airway obstruction is considered an airway emergency and is a challenging clinical scenario for both the otolaryngologist and the anaesthetist. We present three cases of impacted upper airway metallic foreign bodies. Supra-glottic airways were obstructed and precarious. Apnoeic oxygenation utilizing high-flow nasal oxygen (HFNO), a form of tubeless anaesthetic, was used in all three cases, leading to the safe removal of the foreign bodies. Increased training, awareness and equipment availability to provide HFNO apnoeic oxygenation in the emergency setting for otolaryngology airway procedures will lead to better outcomes for patients and decreases the risk of a potential surgical airway. Metallic foreign body airway obstruction is considered an airway emergency and is a challenging clinical scenario for both the otolaryngologist and the anaesthetist, particularly when these cases present in children. Most cases of upper airway foreign bodies occur in children under the age of five , with anWe present three emergency cases in which metallic foreign bodies in the upper aerodigestive tract prevented endotracheal intubation. Apnoeic oxygenation using high-flow nasal oxygenation was used as a safe alternative in all three cases.The first case is of a 7-year-old child presenting with a history of barbed wire inhalation. X-ray imaging of his neck and chest showed a radio-opaque object visible in the upper airway with sharp edges  and 2. DThe second case involved a 3-year-old child who presented with sudden onset noisy breathing. Inspiratory stridor was evident on examination. Radiographs of the neck again showed a radio-opaque object in the upper airway . ApnoeicThe final case is of a 75-year-old female who presented to hospital after inhalation of her dentures  and 7. AMetallic foreign bodies in the upper aerodigestive tract present a difficult emergency scenario for both otolaryngologists and anaesthetists. Laryngeal foreign bodies can be especially complicated to manage, with an increased risk of airway obstruction and risk of requiring a surgical airway . These oApnoeic oxygenation using HFNO is a novel technique, which is being increasingly utilized in laryngeal procedures . The tecA previous randomized controlled trial comparing the use of standard nasal oxygenation with HFNO to allow for apnoeic oxygenation in the removal of foreign bodies during bronchosocopy showed a statistically significant higher level of oxygen saturation and lower level of end tidal carbon dioxide levels in the immediate post-operative period for those in the HFNO group. The use of HFNO has also been shown to have decreased rates of post-operative atelectasis .In light of the novelty of HFNO for apnoeic oxygenation, as well as the associated high stress environment of difficult airway management in the emergency setting, consideration must be given for the anaesthetic experience and familiarity with this technique. HFNO is delivered through specific devices designed to provide humified oxygen at an increased rate. As a result, lack of equipment availability may further hinder the use of this oxygenation method. Increasing training and awareness of this technique will lead to increased accessibility to HFNO in the emergency setting, which may be greatly beneficial in the successful removal of foreign bodies from the upper aerodigestive tract in both the paediatric and adult population.No conflicts of interest. Informed patient consents obtained.None.


The neuron loss caused by the progressive damage to the nervous system is proposed to be the main pathogenesis of neurodegenerative diseases. Ependyma is a layer of ciliated ependymal cells that participates in the formation of the brain-cerebrospinal fluid barrier (BCB). It functions to promotes the circulation of cerebrospinal fluid (CSF) and the material exchange between CSF and brain interstitial fluid. Radiation-induced brain injury (RIBI) shows obvious impairments of the blood–brain barrier (BBB). In the neuroinflammatory processes after acute brain injury, a large amount of complement proteins and infiltrated immune cells are circulated in the CSF to resist brain damage and promote substance exchange through the BCB. However, as the protective barrier lining the brain ventricles, the ependyma is extremely vulnerable to cytotoxic and cytolytic immune responses. When the ependyma is damaged, the integrity of BCB is destroyed, and the CSF flow and material exchange is affected, leading to brain microenvironment imbalance, which plays a vital role in the pathogenesis of neurodegenerative diseases. Epidermal growth factor (EGF) and other neurotrophic factors promote the differentiation and maturation of ependymal cells to maintain the integrity of the ependyma and the activity of ependymal cilia, and may have therapeutic potential in restoring the homeostasis of the brain microenvironment after RIBI or during the pathogenesis of neurodegenerative diseases. Neurodegenerative diseases are supposed to be caused by the abnormal structure and function of neurons ; they maIonizing radiation has been applied to “open” the BBB for drug delivery  or anti-Ependyma is a monolayer of ciliated cuboidal ependymal cells lining the inner surface of cerebral ventricles and canalis spinalis that participates in establishing the essential exchange interface between brain interstitial fluid (BIF) and cerebrospinal fluid (CSF) . A recenThis article will review the physiological roles of ependyma in maintaining brain microenvironment, the pathological roles of dysfunctional ependyma in the pathogenesis of neurodegenerative diseases and RIBI, and the neurotrophic factors and signaling pathways influencing ependymal function. By maintaining the structure and function of ependyma at the early stage of neurodegenerative diseases, valuable therapeutic strategies could be designed to control the pathogenesis of those diseases and prevent dementia and dyskinesia.Ependymal cells (ECs) line the ventricles and the central canal of the spinal cord , formingTanycytes are highly specialized ECs that play a vital role in forming the ependyma of the circumventricular organs (CVOs) . Often dThe CSF produced in the brain ventricular system flows into the subarachnoid space through the median and lateral foramen of the fourth ventricle . From heNeurodegenerative diseases are associated with the abnormal transportation of metabolites or other substances among intracellular fluid, interstitial fluid, CSF and blood in the brain . CSF is The filtration of water through ependyma is mainly controlled by aquaporin 4 (AQP4), the most abundant aquaporin in the mammalian brain . IncreasThe normal activity of the ependymal motile cilia ensures the necessary CSF circulation to maintain brain homoeostasis, wash out toxins, deliver signal molecules and orient the migration of new-born neurons . HoweverThe neurodegenerative diseases share similar changes in the brain at the early stage, such as hydrocephalus  and ventSimilarly, the early diagnosis of PD, especially the premotor phase, is difficult in a clinic setting. Intracellular accumulation of the α-syn aggregates is the major pathological change of PD . A previHD is a genetic neurodegenerative disease caused by the abnormal expansion of the CAG trinucleotide repeat in the huntingtin gene, which leads to a polyglutamine strand at the N-terminus of huntingtin protein . CurrentUnder most circumstance, preventing neuroinflammation at an early stage can improve the cognitive impairment ,113. HowAs a protective barrier lining the brain ventricles, the ependyma is extremely vulnerable to cytotoxic and cytolytic immune responses. The low-dose ionizing radiation showed obvious benefits on the cognition and behavior of severe AD patients in a clinical trial . It is sBesides the local microglia, the infiltrated cytotoxic immune cells  and the In the acute phase of meningitis, the complement fragments and other immune factors in CSF can promote the infiltration of phagocytes and destroy the BCB by forming the cytotoxic and cytolytic attack complexes . In neurIn summary, neuroinflammation can be caused by many reasons including brain infection, acute neuron loss of RIBI, metabolite aggregation, autoimmune diseases and others. The activation of the complement system may indicate the inflammatory status of ependyma together with other factors. As discussed above, BCB dysfunction can be caused by the neuroinflammatory factors, cerebral microvascular disorders, circadian disruption and others. The dysfunction of ependyma, the most important layer of BCB, may largely be involved in BCB dysfunction and lead to the imbalance of brain microenvironment. Similarly, the onset of other neurological diseases may also involve the dysfunction of BCB and the imbalance of cerebral microenvironment, such as the abnormal synaptic activity in epilepsy . As summThe transcriptomic analysis shows that the ECs express several stem-cell-related genes, suggesting that the ECs may be potential neural stem cells that can proliferate and differentiate into scar-forming astrocytes after brain injury ,32. HoweKojima et al. also demonstrated that the continuous intrathecal administration of epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2) significantly stimulated the proliferation of ependymal precursor cells and expansion of ECs and astrocytes in adult rat spinal cords ,163. O’H2+ dependent signal pathway [Intraventricular injection of EGF induces continues extracellular-signal-regulated kinase (ERK) and cyclic AMP response element-binding protein (CREB) activation in the progenitor cells and ECs, which may contribute to the intense periventricular cell proliferation . The act pathway . Many Wn pathway . In the  pathway . GSK3β i pathway ,180,181.The ECs in postnatal and adult spinal cord express the Wnt proteins and the Wnt/β-catenin signaling target gene Axin2 ,175. Wnt2+ wave (ICW) propagation [The Wnt signaling pathway also plays a role in the development and maintenance of ependymal motile cilia ,176. Thepagation ,189,190.pagation ,87,189 apagation .The inhibition of GSK-3 and the associated activation of Wnt/β-catenin signaling could increase astroglial migration, reduce astroglial apoptosis and enhance axonal growth to promote motor function recovery following the spinal cord injury ,193. TheEpendymal cells serve important sensory and mechanical functions, including signal transduction, movement of CSF and insulation of neural tissues from peripheral hazardous substances . AbnormaIt must be emphasized that our current understanding of the roles of ependyma in the normal brain and pathophysiological changes of the brain is still very limited. The direct link of the pathological changes of ependyma to each neurodegenerative disease remains unclear. The long-term effect of radiation damage on the ependyma still needs to be investigated. The therapeutic effect of neurotrophic factors or growth factors on maintaining or restoring ependymal function during the pathogenesis of neurodegenerative diseases or after irradiation also needs to be studied further. Whether neurotrophic factors or growth factors initiate or promote the expression of FoxJ1 in the neural stem cell or progenitor cell to induce the proliferation, differentiation and maturation of ECs remains to be elucidated.