Burning mouth syndrome (BMS) is a chronic debilitating oral condition characterised by a burning sensation of the oral mucosa in an otherwise apparently normal person. Its aetiology and pathogenesis are obscure, but both psychogenic factors and peripheral and central neuropathies appear to be implicated. There is no cure for BMS, and treatment with either local or systemic medications focuses on the relief of symptoms and on improving quality of life. In recalcitrant cases, psychological/psychiatric intervention may be helpful. In order to improve treatment outcomes, a better understanding of the pathogenesis of this syndrome might provide a basis for the development of more effective management strategies. In this short review, we discuss current knowledge of the diagnosis, aetiopathogenesis, and management of BMS.  The International Association for the Study of Pain (IASP) has described burning mouth syndrome as a chronic condition characterised by a burning sensation of the oral mucosa for which no cause can be found . The antThe burning sensation of BMS is moderate to severe in intensity, is usually bilaterally symmetrical, and is present every day for most of the day. It is minimal or even absent early in the morning and during mealtimes and it seldom interferes with sleep. In most cases, BMS starts spontaneously , 4–7 andThe worldwide prevalence of BMS is unknown because nearly all studies have been of European or North American populations and different diagnostic criteria have been used in different studies . The freA diagnosis of BMS can be made only if the oral mucosa is clinically normal and all systemic and local causes for a burning sensation have been excluded , bearingBMS is frequently associated with stressful life events, anxiety, and depressive disorders , 14, andSystemic and topical medications  have beeThe chronic burning sensation of BMS has the characteristics of neuropathic pain and is debilitating with a negative impact on quality of life . As atteWith BMS, there are no clinical signs, and as results of laboratory investigations are usually unremarkable, clinicians who are not familiar with BMS often regard the patient as merely emotionally unstable and the complaint is often not taken seriously. This perceived lack of interest only increases the patient's anxiety which in turn increases perception of the pain of BMS –19. ManaIt is evident that there is a strong link between BMS and the psychic status. The cause-and-effect relationship between depression, anxiety or neuroticism, and BMS is not clear as the psychic factors may be either causative of or consequential to the oral symptoms , 10. TheOne functional magnetic resonance imaging (fMRI) study suggests that in subjects with BMS painful thermal trigeminal stimuli generate different patterns of brain activation in terms of their location and amplitude when compared to healthy control subjects without BMS . FurtherSome pain modulating neural pathways descending from the cortex, hypothalamus, midbrain, and medulla to the spinal cord, influenced by emotional states such as excitement, stress, anxiety, or depression, can either potentiate or suppress spinal nociceptive pathways and may also have the capacity to spontaneously induce nociceptive signals without peripheral input , 24. ThiThe descending inhibitory pathways of this conditioned pain modulatory system are mediated by serotonin, noradrenalin, gamma aminobutyric acid (GABA), and enkephalins. Thus, both a nonpharmacological approach  and pharmacological agents targeting neuronal central sensitization pathways , GABA receptor agonists, and N-methyl-D-aspartate (NMDA) receptor antagonists), alone or in combination, are beneficial in the treatment of neuropathic pain conditions, including BMS .Persistent pain which does not significantly respond to treatment, such as in the case of BMS, is debilitating in that it negatively affects the psyche, evoking feelings of vulnerability, helplessness, and desperation partly because of the fear that the pain will never let up or might even become worse. Such negative emotions can overwhelm the BMS sufferer causing anxiety and depression, interfering with everyday activities, and significantly reducing the quality of life . BMS paiAdditional research is necessary into the roles of genetic factors, familial patterns, and the nature of the complex interactions between stressful life events, personality, comorbid psychic factors, and the lack of social support in the pathogenesis of BMS as it may allow for the identification of predictors of successful treatment , 25.In the pathogenesis of BMS, apart from psychogenic factors, both peripheral and central neuropathies appear to play a role, but the balance between central and peripheral neuropathies varies from case to case . It is pIn persons with BMS who are anxious or depressed and who do not have immediate relief after local anaesthetic regional nerve block, or after topical treatment with capsaicin or with clonazepam, central neuropathy is probably the dominant mechanism of the pain . As in mSeveral neuronal dysfunctions are linked to BMS pain. The lingual mucosa exhibits a decreased number of small-diameter nerve fibres; the remaining small-diameter nerve fibres show upregulation of the transient receptor potential subfamily member V 1 (TRPV1) ion channel, and upregulation of the P2X3 receptors and of nerve growth factor (NGF). These explain the role of trigeminal small-fibre sensory neuropathy in the pathogenesis of BMS , 27, 29.δ and C fibres but also centrally in the dorsal root and trigeminal ganglia. They respond to chemical irritants including the chilli pepper ingredient capsaicin [TRPV1 channels are mostly found in nociceptive terminals of peripheral Aapsaicin . P2X3 ioapsaicin , 32.It has been further proposed that downregulation of central dopaminergic pain-inhibitory pathways also plays a role in the pathogenesis of BMS , 4, 27, In the context of persistent peripheral neuropathy, the central afferent nociceptor terminals in the dorsal horn of the spinal cord release excitatory biological mediators which can activate postsynaptic NMDA receptors which under physiological conditions are silent, thus resulting in central sensitization with increased excitability . There mThus, central sensitization characterised by structural and functional neural plasticity results in increased excitability and increased tonic activity of central nociceptive neurons, playing an important role in the pathogenesis of BMS , 14. HowPatients should be told that BMS is a complex disorder for which there is no cure and treatment is purely symptomatic, and therefore expectations of the outcome of treatment should not be unrealistic . As the Capsaicin is the “hot” component of chilli pepper and has been used both topically and systemically in the treatment of BMS, reportedly to bring about symptomatic relief. Topical capsaicin has the capacity to bind to the TRPV1 ion channels of small-diameter peripheral sensory nerve fibres, mediating desensitization of afferent nociceptors, and causing reversible degeneration of peripheral sensory nerve endings, with consequent reduction in the syndromal burning pain sensation , 30. It Clonazepam, a benzodiazepine, is a GABAnergic agonist, which activates pain-inhibitory pathways in the spinal cord and in peripheral nociceptors. When applied topically to the oral mucosa, clonazepam is thought to decrease excitability of peripheral sensory nerve fibres, and when given systemically, it has central sedative, anxiolytic, and analgesic effects. The use of both topical and systemic clonazepam has been reported to reduce the intensity of the pain of BMS , 35, 36.Antidepressants are often used to treat BMS most probably because of their documented effects in reducing the intensity of neuropathic pain and because of the close association between BMS and generalized anxiety and depressive disorders . StudiesAlpha lipoic acid, a potent antioxidant, has been shown to be beneficial in the treatment of BMS, either alone or particularly in combination with anticonvulsants or with psychotherapy (cognitive behaviour therapy) . The antIndividual or small-group cognitive-behavioural therapy has been shown to reduce the intensity of the pain of the BMS in a significant number of sufferers, either alone or with medications , 37.Cognitive-behavioural therapy is a directed, structured, short-term psychological treatment aimed at correcting dysfunctional emotional responses such as pain, fear, helplessness, vulnerability, or exhaustion, by changing thoughts and behaviours . The ratWith cognitive-behavioural therapy, harmful thoughts and problematic behaviours are identified, and the dysfunctional relationship between cause and disordered emotional response is explained to the patient. An understanding of the mechanisms that drive dysregulated relationships between thought, behaviour, and emotion may decrease the level of anxiety. Cognitive-behavioural therapy can undoubtedly be an effective part of the management of BMS , 25, 37.As it is evident that sometimes psychogenic factors are closely if not causally associated with the neuropathic pain of BMS, and if antidepressant, anxiolytic, or anticonvulsant agents are indicated, then management should be by a psychiatrist.The pathogenesis of BMS is complex involving psychogenic factors and dysregulated peripheral and central pain pathways. Genetic factors determining the function of neural pain pathways may play an important role in individual susceptibility to BMS, and while there is no standard treatment protocol for its management, both drugs and psychological services may be required.


Overall Abstract: The brain-gut-microbiota axis is emerging as a research area of increasing interest for those investigating the biological and physiological basis of neurodevelopmental, age-related and neurodegenerative disorders. The routes of communication between the gut and brain include the vagus nerve, the immune system, tryptophan metabolism, via the enteric nervous system or by way of microbial metabolites such as short chain fatty acids. These mechanisms also impinge on neuroendocrine function at multiple levels. Studies in animal models have been key in delineating that neurodevelopment and the programming of an appropriate stress response is dependent on the microbiota. Developmentally, a variety of factors can impact the microbiota in early life including mode of birth delivery, antibiotic exposure, mode of nutritional provision, infection, stress as well as host genetics. At the other extreme of life, individuals who age with considerable ill health tend to show narrowing in microbial diversity. Stress can significantly impact the microbiota-gut-brain axis at all stages across the lifespan. Recently, the gut microbiota has been implicated in a variety of conditions including obesity, autism, schizophrenia and Parkinson’s disease. Moreover, animal models have been key in linking the regulation of fundamental brain processes ranging from adult hippocampal neurogenesis to myelination to microglia activation by the microbiome. Finally, studies examining the translation of these effects from animals to humans are currently ongoing. Further studies will focus on understanding the mechanisms underlying such brain effects and developing nutritional and microbial-based intervention strategies.


Routing protocols based on topology control are significantly important for improving network longevity in wireless sensor networks (WSNs). Traditionally, some WSN routing protocols distribute uneven network traffic load to sensor nodes, which is not optimal for improving network longevity. Differently to conventional WSN routing protocols, we propose a dynamic hierarchical protocol based on combinatorial optimization (DHCO) to balance energy consumption of sensor nodes and to improve WSN longevity. For each sensor node, the DHCO algorithm obtains the optimal route by establishing a feasible routing set instead of selecting the cluster head or the next hop node. The process of obtaining the optimal route can be formulated as a combinatorial optimization problem. Specifically, the DHCO algorithm is carried out by the following procedures. It employs a hierarchy-based connection mechanism to construct a hierarchical network structure in which each sensor node is assigned to a special hierarchical subset; it utilizes the combinatorial optimization theory to establish the feasible routing set for each sensor node, and takes advantage of the maximum–minimum criterion to obtain their optimal routes to the base station. Various results of simulation experiments show effectiveness and superiority of the DHCO algorithm in comparison with state-of-the-art WSN routing algorithms, including low-energy adaptive clustering hierarchy (LEACH), hybrid energy-efficient distributed clustering (HEED), genetic protocol-based self-organizing network clustering (GASONeC), and double cost function-based routing (DCFR) algorithms. With increasing advances in wireless communication systems, electronics and sensing technologies, wireless sensor networks (WSNs) have recently become an important, indispensable platform for a great number of vital surveillance and control applications . A WSN cWith much more sensor nodes, WSNs are different from the traditional network in many aspects, including the architecture, addressing the method, the communication mode, the routing structure, etc. With the flat routing structure , the routing protocol is presently one of the key technologies in WSNs ,6. In geTopology control is one of the critical strategies for routing protocols in WSNs to improve network longevity. This is dedicated to periodical restoration of network topology in order to achieve the desired connectivity and ensure sufficient routes . NetworkTowards improving WSN longevity, we pay more attention to topology control to form the optimal network structure. However, we abandon the clustering mechanism and propose a dynamic hierarchical protocol based on combinatorial optimization (DHCO) to establish a feasible routing set for each sensor node. The feasible routing set is equivalent to a solution space consisting of many valid routes. The optimal route is obtained from the solution space by using the maximum–minimum criterion, which can be formulated as a combinatorial optimization problem. For the consideration of balancing the energy consumption of sensor nodes, the essence of the DHCO algorithm is to obtain the optimal route for each sensor node from its corresponding feasible routing set. Differently to state-of-the-art WSN routing algorithms , in selecting the cluster head or the next hop node on the basis of the node energy property or the node distance property, the DHCO algorithm employs a hierarchy-based connection mechanism to construct a hierarchical network structure, and utilizes the combinatorial optimization theory to establish the feasible routing set for each sensor node, taking advantage of the maximum–minimum criterion to obtain their optimal route to the base station; this contributes to balancing the energy consumption of sensor nodes and improving WSN longevity. The remainder of this paper is organized as follows. We present related work on routing protocols to improve WSN longevity in p , which forms clusters accordingly. However, the randomized process fails to select certain sensor nodes  as CHs, which results in unevenly distributed CHs and premature energy depletion of these sensor nodes [Clustering routing protocols have been widely researched in WSNs, and have achieved very fruitful results. In the clustering network structure, sensor nodes are divided into several clusters; each cluster is a node set of a cluster head (CH) and a plurality of member sensor nodes. The CH is not only accountable for managing member sensor nodes, but it also presides over data aggregation and data forwarding between clusters. The earliest classical clustering protocol of WSNs is the LEACH protocol , which oor nodes . ConsequIn the past decades, many classical WSN routing protocols utilizing the node energy property to search for the optimal clustering structure have arisen. A representative routing protocol is the stable election protocol (SEP) , which iAlternatively, the node distance property is another significant aspect of developments upon the LEACH algorithm. At present, a great many efficient routing protocols based on the node distance property have arisen, such as the power-efficient gathering in sensor information systems (PEGASIS), energy-efficient unequal clustering (EEUC), and gateway based energy-efficient routing protocol (M-GEAR) algorithms. PEGASIS  is an op(1)The BS and all sensor nodes are stationary after deployment, and are equipped with a Global Positioning System (GPS) unit. Hence, these nodes are location-aware.(2)All properties for each sensor node are identical, while the BS is manually maintained and has enough energy to support continuous operations, with its energy denoted as (3)Provided with sufficient energy, each node can control the transmission power according to the distance between the transmitter and the receiver.(4)The amount of transmission data is exactly equal for each sensor node of valid routes.In the grid-based development field, there are great many randomly distributed sensor nodes. The network topology including all sensor nodes and the BS builds a graph the WSNs ,22:(1)Tht, the residual energy of all sensor nodes is denoted as t is the time scale in terms of transmission rounds of the WSNs [At the transmission round the WSNs . The nei follows :1)rs=1−rs=1−t, tpossible , we condFor the sensor node l-bits message over l-bits message over The radio model follows that in , as showAbove, In this Section, the DHCO algorithm is described in detail. Differently to conventional WSN routing protocols  for selecting the CH or the next hop based on the node energy or the node distance properties, or a combination of these two properties, the DHCO algorithm constructs a hierarchical network structure according to the node distance property, and then utilizes the combinatorial optimization theory to establish the feasible routing set for each sensor node. The feasible routing set for each sensor node, moreover, is equivalent to a solution space. Next, taking advantage of the maximum–minimum criterion, the optimal route is obtained from the solution space on the basis of the node energy property, which ultimately evenly distributes network traffic load to balance the energy consumption of sensor nodes and improve WSN longevity. Therefore, the process of obtaining the optimal route can be formulated as a combinatorial optimization problem.k-layer sensor node subset of In order to construct a hierarchical network structure, we assume that each sensor node is layered and belongs to a specific node set according to the adjacency matrix The hierarchical network structure pth valid route of the feasible routing set The hierarchical network structure To unify formation, let t, the residual energy of the sensor nodes in the feasible routing set t.The feasible routing set In order to obtain the especial sensor node The value of the subscript t, the transmitter Finally, at the transmission round quations  and 5)..t, the tThrough procedures described in ns again ,24.t; the more sensor nodes that were alive, the better the algorithm performed. Another performance aspect was given by the statistics for the transmission rounds of diverse experimental scenarios in WSNs; the more transmission rounds there were, the better the algorithm performed. More details are presented as follows.In this Section, we provide various simulation experiments to demonstrate the effectiveness and superiority of the DHCO algorithm, in comparison—from multiple perspectives—with state-of-the-art WSN routing algorithms such as LEACH , HEED 1, GASONeCFor the simulation experiments, algorithms including DHCO, LEACH, HEED, GASONeC, and DCFR ran on diverse deployment scenarios, for which sensor nodes were randomly distributed and the BS was located at a certain position. For example, in In general, the radio wave propagation was highly variable and difficult to be modeled. Thus, as for the radio model used in , our radIn this subsection, simulation experiments were conducted to compare the percentage of live sensor nodes of the DHCO algorithm with that of LEACH, HEED, GASONeC, and DCFR algorithms for different transmission rounds in WSNs. The sensing field was set to a The number of sensor nodes and the width of the sensing field are critical factors influencing the energy consumption of sensor nodes and the WSN longevity. For diverse widths of the sensing fields and various numbers of sensor nodes, we carried out several simulation experiments, whose results are exhibited vividly by In the deployment scenario of 100 randomly distributed sensor nodes and the BS located at the coordinate , transmission rounds decreased with the increasing width of the sensing field, according to Equation . Thus, tEquation  indicateIn the DHCO algorithm, the most time-consuming procedures were to construct the hierarchical network structure for all sensor nodes and to establish the feasible routing set for each sensor node. For each transmission round, the mean time (in s) and the standard deviation of the computational complexity for the DHCO algorithm were accurately calculated. In consideration of various numbers of sensor nodes, In In this paper, we propose a DHCO algorithm to balance the energy consumption of sensor nodes and to improve WSN longevity. Compared with state-of-the-art WSN routing algorithms, including LEACH, HEED, GASONeC, and DCFR, the DHCO algorithm constructs a hierarchical network structure based on the node distance property and establishes the feasible routing set that provides the solution space; these are the foundations for the formation of a combinatorial optimization problem. Taking into account the node energy property, the DHCO algorithm takes advantage of the maximum minimum criterion to obtain the optimal route for each sensor node from their corresponding solution spaces. Diverse experimental results demonstrated that the DHCO algorithm is feasible and has superior performance over the existing WSN routing algorithms with respect to balancing the energy consumption of sensor nodes and improving WSN longevity. Finally, as future work, this can be extended for the WSNs with sensor nodes that follow a mobility pattern; this is a significant subject differing from the current WSNs, for which the sensor nodes follow a mobility pattern.


Girth weld cracking is one of the main failure modes in oil and gas pipelines; girth weld cracking inspection has great economic and social significance for the intrinsic safety of pipelines. This paper introduces the typical girth weld defects of oil and gas pipelines and the common nondestructive testing methods, and systematically generalizes the progress in the studies on technical principles, signal analysis, defect sizing method and inspection reliability, etc., of magnetic flux leakage (MFL) inspection, liquid ultrasonic inspection, electromagnetic acoustic transducer (EMAT) inspection and remote field eddy current (RFDC) inspection for oil and gas pipeline girth weld defects. Additionally, it introduces the new technologies for composite ultrasonic, laser ultrasonic, and magnetostriction inspection, and provides reference for development and application of oil and gas pipeline girth weld defect in-line inspection technology. Oil and gas pipelines are the main arteries of the national economy; pipeline safety is closely related to people’s lives, social and economic development. Although pipeline transport is the safest and most reliable means of transporting for flowing mediums, leakage occurs every year due to welding defects, corrosion and local damage, resulting in severe losses or personal injury and even death. Among them, due to the limited technical level of the construction period, on-site welding construction, operating environment and other factors, girth weld has always been a weak part of the pipeline, which made girth weld cracking one of the main failure modes of oil and gas pipelines. Among the failure accidents in 2010–2012, as released by the US Department of Transportation Pipeline and Hazardous Materials Safety Administration, up to eight accidentswere caused by the girth weld cracking of gas transport pipelines (regardless of perforation caused by girth weld corrosion), three of the accidents occurred in the new commissioning pipeline , in ordeThe girth weld defects of oil and gas pipelines can be roughly classified into planar defects, volumetric defects and irregular shape defects. Planar defects include incomplete penetration, lack of fusion, crack and undercut, etc. Incomplete penetration refers to the gap between base materials caused by insufficient arc welding; lack of fusion results from the insufficient fusion and bonding between weld metal and base material or between weld metals under several passes. The former is also known as lack of side fusion, while the latter is called lack of inter-run fusion. A crack appears in the weld during or after cooling under the welding stress or the residual stress of formation. The lack of fusion and crack defects of pipeline weld are shown in Volumetric defects include porosity, slag inclusion, underfill, bevel grinding and weld corrosion, etc. Porosity is air pores formed when the air generated in the process of welding fails to escape but remains inside weld metal. Slag inclusion occurs when the slag of welding flux fails to float out of the weld pool and is trapped in the weld pool during the melting–cooling process. Porosity and slag inclusion often occur inside weld metal. Irregular shape defects contain an irregular weld outline, and mismatched weld joint, etc. A mismatched weld joint means that the two edges of the pipeline are mismatched during welding  , but it Ultrasonic inspection is presently an important nondestructive testing technology for pipeline girth weld defect inspection. Ultrasonic waves could be scattered by planar and volumetric defects, and the echo signals from defects can be utilized to identify two such types of defects, measure the dimension and depth of defects and judge the nature of defects. Regular ultrasonic manual or fully-auto inspection has been widely applied in the detection of pipeline weld imperfections. Along with the increasing requirements for the ability to inspect the small weld defects, some advanced ultrasonic inspection technologies have been developed, such as phased array ultrasonic inspection  and timeCommon on-site weld defect inspection technologies are applied in the girth weld defect inspection during pipeline construction or after pipeline excavation. However, advanced oil and gas pipeline in-line inspection technology is still needed to inspect the defects of long-distance transport pipelines in operation, which have multiple girth welds, so as to realize the overall girth weld defect inspection of long-distance transport pipeline. For nearly three decades, multiple technologies have been developed and applied in the inspection of oil and gas pipeline defects, including corrosion, stress corrosion and crack, such as, high-resolution MFL inspection , liquid The principle of defects detecting and sizing of MFL inspection equipment is based on the varying magnetic lines of defects on the pipeline ; it coulThe axial magnetic leakage field component of a metal loss defect is a typical uni-polar waveform, and its amplitude is highly related to defect depth, but the axial signal has nonlinear change in the directions of width and length, so the length and width of defects can only be estimated based on the range of signal deformation, causing very low accuracy and reliability. The radial signal component shows bipolar sine waveform with equal amplitude of peak and trough, which is highly correlated with defect depth. The gap between peak and trough can greatly reflect the length of the defect. The circumferential signal shows the positive and negative polarities in both radial and circumferential directions, and visually reflects the width and length of the defect . This teIn recent years, Kinder Morgan , TransCanada  and PetroChina Pipeline Company  are engaging in the application of MFL in-line inspection technology in the inspection and research of girth weld defects . As reveEfforts are still being made to study and explore the application of MFL in-line inspection technology in the inspection and sizing of girth weld crack defects. Liu et al.  built a At present, a lot of research work has been done in the field of signal analysis and quantitative analysis of three-axis high-resolution MFL. The main analysis methods include finite element analysis, neural network and so on.(1) Finite Element AnalysisIn the defect sizing of MFL inspection, the ANSYS modeling of finite element analysis is employed to study the relationship between geometric parameters and MFL signals for pipeline defects. Ding Zhanwu et al.  pointed (2) Neural NetworkThe application of a neural network in approaching the functional relationship between geometrical parameters and MFL signals of a defect has become a hot topic of research, and has made great progress. Shen-Tun Li put forward the defect pattern recognition method for nondestructive testing based on fuzzy subset theory, and applied the radial basis function neural network in the interpolation calculation and non-linear approximation of a magnetic leakage field. Also, he created a radial basis function (RBF) network model and proposed the learning algorithm, so as to provide a feasible method for pipeline defect sizing . R. ChriWith regard to the domestic studies on the neural network of a pipeline defect, Wang Taiyong et al. ,41 emploThe three-axis high-resolution MFL inspection for the volumetric defects (corrosion and scratch) of long-distance transport pipelines has the dimensional accuracy of ±10%, and its confidence level exceeds 90%, so it can satisfy the regular needs of the inspection of volumetric defects in oil and gas pipelines ,46. NeveIn the reliability evaluation of simulated girth weld defect inspection for cracks, there were 102 defects, including seven defects to the report threshold of MFL in-line inspection and 39 defects (accounting for 38.2%) indicated in the MFL signal. The accuracy of all defect depths was within 25% wt, but it required the defect width at least 0.25 mm. Three-axis high-resolution MFL inspection technology could poorly detect girth weld crack defects and had poor accuracy of defect sizing, so it had some limitations. It should be noted that varying wall thickness, skewed weld and mismatched weld joint affect the signal identification of the girth weld defect significantly, and it is now very difficult to differentiate the signals of girth weld defects and mismatched weld joints.Based on the girth weld defect signal of three-axis high-resolution MFL inspection for a crude oil pipeline (X65), the excavation examination was conducted at those 32 defects in a focused manner, including lack of fusion/incomplete penetration at eight positions, missing cap at 10 positions and other defects at 14 positions. The defect depth deviation was ±6%, and the confidence level was 90%. A gas pipeline was cut for girth weld defects at 13 positions, including lack of fusion at 11 positions, which were all detected through MFL4, but crack defects at two positions (with an opening of 0.3 mm) were not detected. The deviation of the defect depth for lack of fusion in girth weld during MFL4 in-line inspection was ±15%. The defects with the opening width of 0.3 mm could not be detected in MFL4.MFL inspection has some limitations for the crack defects of girth weld, but it does not need a coupling agent, and is able to detect the girth weld defects of gas pipelines as well as many types of defects. Hence, it is comprehensively concluded that this technology is the first choice for baseline screening of girth weld defects.Ultrasonic crack inspection equipment can identify tiny cracks ,48, streCrack ultrasonic inspection equipment follows the principle of ultrasonic measurement based on pulse echo time technology. In the common ultrasonic nondestructive testing technology, 45° wave technique is successfully utilized to achieve the axial crack ultrasonic inspection of pipelines. This technology employs ultrasonic sensors to transmit the ultrasonic waves into pipe wall at a specified incident angle. When ultrasonic waves encounter any reflective characteristics , some ultrasonic waves are reflected back to the original position . By asseAt present, this technology has not been applied in the practical girth weld defect inspection of pipelines in other countries. Through cooperation with GE PII, PetroChina Pipeline Company  has carried out a series of studies  and imprDuring identification, the girth weld defect is comprehensively analyzed based on the signals of C-scan view, overlap view, and 3D view . Figure Theoretically, the physical measurement of defect depth is conducted based on the number of sampling points. In the experiment process, the zero position of the sensor and the difference between the acoustic velocities of ultrasonic waves in the base metal and weld have a significant influence on the accuracy of the experiment. Hence, it is necessary to calibrate the acoustic velocity during the experiment, and determine the zero position of the sensor, which is a very complicated process. The neural network intelligent method can simplify the experiment process, and be applied in the defect sizing of long-distance transport pipelines. Masnata and co-workers  made 135Liquid ultrasonic inspection technology achieves satisfying results in the inspection and defect sizing of axial cracks (stress corrosion crack and fatigue crack) in long-distance transport pipeline, so as to effectively lower the risk of an axial crack in the pipeline ,58,59,60Based on the results of liquid ultrasonic crack inspection for a pipeline, 42 defects were selected for excavation verification ,24. For EMAT technology follows the principle of electromagnetic induction eddy current to generate ultrasonic waves, and its converter can be kept separate from the surface of the inspected object, and does not require any coupling medium. In addition to its suitability for sulfide corrosion crack (SCC) crack detection, it will enjoy a bright future in the in-line inspection of oil and gas pipelines.EMAT inspection technology is also known as eddy current-acoustic inspection technology, and its inspection principle is presented in Common ultrasonic and electromagnetic ultrasonic technology share many similarities  except tTransCanada, a Canadian company, started an attempt associated with PII to apply the EMAT technology in pipeline inspection equipment , and empThe inspection of a girth weld crack is similar to that of a longitudinal weld crack, but it is relatively more difficult to inspect the circumferential crack. PetroChina Pipeline Company and PII carried out the feasibility study on the EMAT inspection technology and equipment for pipeline girth weld defects, and employed the axially arranged EMAT converter based on the characteristics of a pipeline girth weld defect . To guarNow, international studies on electromagnetic ultrasonic signal focus on the suitable signal processing methods, such as, wavelet conversion, to eliminate noise and identify the defect. The band-pass filter based on discrete Fourier transform can be utilized to effectively eliminate electronic noise, but this method becomes ineffective when the frequency of the input signal varies with time, and loses the information on time domain of signal peak . The timYang Han et al.  demarcatBased on the problem of girth weld crack defect inspection for long-distance natural gas transport pipelines, PetroChina Pipeline Company is cooperating with GE Oil & Gas Pipeline-inline-inspection Solutions  to conduct the preliminary study on the EMAT inspection technology of girth weld crack defects. Nevertheless, the reliability of EMAT inspection for girth weld crack defects has not been publicly reported. Hence, the reliability of EMAT inspection for pipeline axial cracks is introduced for reference.TransCanada  Pipeline generalized the data of electromagnetic ultrasonic inspection for axial cracks and stress corrosion cracks (SCC) in 13 pipelines from 2008 to 2011 . The resKinder Morgan studied the reliability of EMAT inspection for axial cracks of pipelines . The EMAIn 2008, Pipeline Research Council International (PRCI) initiated a program for assessment of EMAT in-line inspection performance, and employed the technologies including magnetic particle, ultrasonic inspection, phase-array ultrasonic imaging and crack interruption to compare the size of a pipeline defect from EMAT in-line inspection with the data of field excavation inspection . After cIn recent years, remote field eddy current (RFEC) inspection has been an important technology for natural gas pipeline girth weld crack defect inspection. Reference  reportedElectromagnetic eddy current in-line inspection technology can effectively receive the magnetic field that passes the tube wall and returns to the inside tube by employing the excitation coil or placing a measurement coil with a certain distance from the excitation coil, so as to effectively detect the interior wall defect of the metal tube. The inspection principle is as shown in Unlike the common eddy current testing which is the impedance plane analysis form, the remote field eddy current (RFEC) technique reduces problems such as lift-off. As the excitation source frequency is generally low, RFEC does not have the skin effect, and the RFEC signal is not sensitive to the lift-off effect. With the same inspection sensitivity to crack defects on the inner and outer surfaces of pipelines, it can effectively overcome the limitations of the common eddy current inspection method, so it is more suitable for the inspection of natural gas pipeline surface cracks. JENTEK Sensors Inc., a U.S. company, has developed the electromagnetic eddy current technology with a magnetic winding meter (MWM) array to improve the identification of imperfections sensitive to lift-off value, which has been proved to be suitable for the identification and sizing of axial cracks in oil and gas pipeline. In the stress corrosion crack inspection, the technology has been verified to excel other inspection methods in the possibility of detection (POD), lift-off value modification and speed modification, etc. . RFEC inThe RFEC technology with the traditional sine excitation also has some limitations, such as, weak signal, slow speed and low rate, and the sine excitation signal causes very high power consumption at sensors ,93. BaseElectromagnetic RFEC inspection is carried out to detect imperfections based on the signal phase difference rather than signal amplitude, and the phase difference between signals has an approximate linear relationship with defect depth . Wu DehuFor defect sizing in pulsed RFEC inspection, Yang Binfeng et al. ,103 and RFEC inspection technology can detect the defects on the surface of natural gas pipelines without being significantly affected by lift-off and eccentricity, etc. Nevertheless, the RFEC inspection signal is weak and slow, so its overall inspection efficiency is very low. For this reason, RFEC technology should be further studied in the future.To improve the accuracy of pipeline defect inspection, domestic and overseas science and technology personnel are constantly exploring the new pipeline defect inspection methods, including Pulse echo (PE)/TOFD composite inspection technology, laser ultrasonic, magnetostriction, and other contactless inspection technologies, which have great potential of application in the long-distance transport pipeline girth weld defect inspection. Hence, these technologies are briefly described in the following sections.Statoil  has deveLaser ultrasonic inspection is a new technology, popular in recent years. Ultrasonic waves are generated on the surface of the inspected work piece by pulsed laser beam irradiation. After changing the experimental parameters, the laser ultrasonic source can induce many kinds of guided waves, including longitudinal wave, lateral wave and surface wave. The ultrasonic signal can be generated by laser excitation and detected by the optical method, so it can realize completely contactless inspection and quick scan imaging, and facilitate the realization of nondestructive testing under adverse conditions, e.g., high temperature and strong vibration . AdditioMagnetostriction is an innate feature of ferromagnetic materials. The magnetostriction effect and its reverse effect can be utilized to generate and receive the ultrasonic guided waves inside ferromagnet. A magnetostriction sensor can be utilized to detect the crack, corrosion and other defects of wire rope, metal rod, pipe and plate ,113. EveThree-axis high-resolution MFL inspection technology can identify a lot of long-distance transport pipeline girth weld defects. It is highly adaptive and able to effectively detect the volumetric defects, but the accuracy of defect sizing is not high.Neither three-axis high-resolution MFL inspection nor liquid ultrasonic inspection can effectively detect the closed crack defect of long-distance transport pipeline girth weld, except the defects with a large opening (about >0.5 mm).The future development will focus on improving the existing electromagnetic ultrasonic crack inspection and RFEC inspection, developing and applying new crack inspection technology and realizing the effective inspection of girth weld crack defects.Due to the complexity of the on-line inspection condition and the principle of detection technologyfor long-distance transport pipeline girth weld, it is very difficult to detect and quantify the girth weld defects. The irregular outline of girth weld, surface condition of pipeline and other factors have inevitable influence on the inspection and sizing of girth weld defects, and attention should be paid to the actual pipeline inspection factors during inspection data analysis and sizing.At present, the finite element method and the neural network method are used to quantify the defects of girth welds, but the accuracy is far from satisfying the requirements. The type and sizing of defects need to be studied systematically.In order to improve the accuracy of pipeline defect inspection, the new technologies for contactless inspection have been applied in the in-line inspection of pipeline defects, including composite inspection, laser ultrasonic and magnetostriction.This paper analyzes the characteristics of long-distance transport pipeline girth weld defects, and summarizes the inspection principle, defect signal identification, defect sizing method and inspection reliability of existing girth weld defect in-line inspection technologies systematically, as well as the new technology of pipe defect in-line inspection. It is comprehensively concluded that:


Perivascular fat, the cushion of adipose tissue surrounding blood vessels, possesses dilator, anti-contractile and constrictor actions. The majority of these effects have been demonstrated in vitro and may depend on the vessel and/or the experimental method or species used. In general, the relaxant effect of perivascular adipose tissue is local and may be either endothelium-dependent or endothelium-independent. However, nerve stimulation studies show that, in general, perivascular adipose tissue (PVAT) has an anti-contractile vascular effect likely to involve an action of the autonomic vascular nerves. Apart from a direct effect of perivascular fat-derived factors on bypass conduits, an interaction with a number of neurotransmitters and other agents may play an important role in graft performance. Although the vascular effects of PVAT are now well-established there is a lack of information regarding the role and/or involvement of peripheral nerves including autonomic nerves. For example, are perivascular adipocytes innervated and does PVAT affect neuronal control of vessels used as grafts? To date there is a paucity of electrophysiological studies into nerve-perivascular fat control. This review provides an overview of the vascular actions of PVAT, focussing on its potential relevance on blood vessels used as bypass grafts. In particular, the anatomical relationship between the perivascular nerves and fat are considered and the role of the perivascular-nerve/fat axis in the performance of bypass grafts is also discussed. CABG surgery is an effective means of restoring blood supply to the myocardium in cases where flow through a coronary artery is reduced or blocked due to atherosclerosis. A number of different blood vessels have been used for revascularization including the internal thoracic artery (ITA), radial artery (RA), gastroepiploic artery (GEA) and the saphenous vein (SV). Currently the ITA, RA and SV are the most commonly used vessels and, of the three, the SV is the most frequently used. There are a number of reasons for this. The use of autologous grafts eliminates problems of tissue rejection and the need for tissue typing and matching. The SV also has a number of practical advantages: it is expendable, since lower limb venous drainage can rely solely on the deep venous system; its superficial position renders it easily accessible, facilitating its exposure at harvest   at http:Favaloro  and its Favaloro . Another2 whereas, in general, veins are subjected to lower pressures of ~5–8 mmHg, a non-pulsatile flow and a shear stress of ~0.2 dyne/cm ; the intima, the media and the adventitia. The muscular arteries used as bypass grafts have a well-defined internal elastic lamina (IEL) at the inner region of the tunica intima and a diffuse external elastic lamina (EEL) bordering the media and adventitia. The intima consists of a thin basement membrane and its endothelial lining. Elastic fibres are scattered within the media, which is mainly composed of vascular smooth muscle cells (VSMCs) and collagen. A microvascular network, the vasa vasorum, is mainly confined to the outer adventitial layer although extending into the media. Also, mainly located in the adventitia, are the autonomic or perivascular nerves. The human SV, which is a subject of particular interest here, has a muscular wall consisting of several layers of VSMCs separated by layers of collagenous connective tissue. The tunica media and intima also contain a few elastic fibres but there is no distinct IEL or EEL as in arteries of similar size. The outermost layer, the adventitia, is broad consisting mainly of collagen fibres and fibroblasts that merge with the surrounding connective tissue and perivascular adipose tissue (PVAT) Fig. . The vas  and mechanical  stimuli. A small proportion of vein afferent nerves responded to ‘noxious  stimuli’ suggesting that they may potentially encode nociceptive information from the vein, especially under pathological conditions (e.g. such as the increased inflammatory cytokine levels that occurs in failing bypass grafts)  receptor-mediated contractions evoked by ATP are significantly lowered in varicose SVs compared to those from patients with obliterating atherosclerosis; it has been suggested that P2-receptors may therefore be involved in the pathogenesis of varicose vein disease  as well as at regions of high density vasa vasorum, and, in the case of diseased vessels, at regions of neovascularization , may indicate the existence of such a neuron/axon-adipose cell neuroeffector mechanism. Whether similar mechanisms can be related to the sympathetic nerve/axon contacting lipids in Schwann cells remains unknown at this stage. However, it has been shown that leptin can increase sympathetic efferent signalling to white adipose tissue to increase lipolysis . Future functional/electrophysiological studies are required to determine the influence of the nerve-PVAT axis on graft performance. While a small number of in vitro studies on animal vessels have provided useful information, similar studies using human vessels are needed in an attempt to determine the functional relationship of the perivascular nerves and adipose tissue and the role this axis may play in the performance of bypass grafts.


The prospects for cell replacement in spinal cord diseases are impeded by inefficient stem cell delivery. The deep location of the spinal cord and complex surgical access, as well as densely packed vital structures, question the feasibility of the widespread use of multiple spinal cord punctures to inject stem cells. Disorders characterized by disseminated pathology are particularly appealing for the distribution of cells globally throughout the spinal cord in a minimally invasive fashion. The intrathecal space, with access to a relatively large surface area along the spinal cord, is an attractive route for global stem cell delivery, and, indeed, is highly promising, but the success of this approach relies on the ability of cells (1) to survive in the cerebrospinal fluid (CSF), (2) to adhere to the spinal cord surface, and (3) to migrate, ultimately, into the parenchyma. Intrathecal infusion of cell suspension, however, has been insufficient and we postulate that embedding transplanted cells within hydrogel scaffolds will facilitate reaching these goals. In this review, we focus on practical considerations that render the intrathecal approach clinically viable, and then discuss the characteristics of various biomaterials that are suitable to serve as scaffolds. We also propose strategies to modulate the local microenvironment with nanoparticle carriers to improve the functionality of cellular grafts. Finally, we provide an overview of imaging modalities for in vivo monitoring and characterization of biomaterials and stem cells. This comprehensive review should serve as a guide for those planning preclinical and clinical studies on intrathecal stem cell transplantation. While several clinical trials report therapeutic benefit,4 many other trials report good safety profile but no efficacy,7 triggering the closing of some cell-manufacturing companies. Such disappointing clinical translation results can be attributed to the large difference in the size of the CNS between mice and humans, as the mouse brain is 1000 times smaller. The issue of cell distribution in the large CNS must be addressed prior to the pursuit of more clinical research. Herein, we discuss the current clinical needs and solutions that have been used in cell-based therapies, with a particular focus on targeting the spinal cord. Recent reports dealing with hydrogels and nanoparticles for cell delivery to the CNS are also reviewed. The modulation of the microenvironment of cell-laden hydrogels with the use of nanoparticles and engineering strategies to allow in vivo imaging are also discussed in depth.Central nervous system (CNS) diseases and injuries are some of the most devastating for patients. The complexity and role of the CNS is such that its functional deterioration results in a huge impact on the quality of life, as well as an enormous financial burden to society. Cellular degeneration and death are the most common features of CNS disorders. In that way, several approaches that have attempted to regenerate cells, tissues, or organs in order to restore or establish normal function have been studied. In many instances, transplanted stem cell suspensions were shown to be highly therapeutic in small-animal models,8 and intra-arterial9 routes are very promising for the delivery of stem cells to the brain. However, efficient delivery of stem cells to the broad areas of the spinal cord needs still to being resolved. There are several gateways to the spinal cord that have been considered, including the central canal, the intra-arterial, the intraparenchymal, and/or the intrathecal routes. Schematic representation of the cell/biomaterial constructs delivery routes into the spinal cord is depicted in Fig. Intraventricular10 and thus, this route of cell delivery should be pursued clinically only after extensive research on large animals  circulation following injection of stem cells could lead to a very debilitating disorder, syringomyelia,als Fig. .11 Considering that most of the potential targets for therapy are within the cervical spine, any vascular occlusion or injury in this area may result in severe neurological deficits that could affect most of the body, including tetraplegia. In this context, the intra-arterial route for cell delivery to the spinal cord should be considered with extreme caution  and easy access speaks in favor of using the extraspinal space as a route of cell delivery.17 Thus, if this route were effective, it could immediately be applied worldwide; however, several challenges need to be addressed before this approach can become a clinical reality. The most important is that the cells deployed to the CSF need to traverse the pia matter and enter the parenchyma of the spinal cord in the desired region. There is strong evidence about ability of the cells to migrate from the CSF compartments into parenchyma on early stage of development;2 however, adult or aging pia matter will likely be more challenging barrier to traverse. Some potential solutions to this challenge could be engineering the cells for expression of metalloproteinases18 or supplementation of biomaterials with enzymes selectively targeting collagen and reticular fibers of pia. The second challenge is that the cells injected as a suspension  proteins, can direct cell behavior by providing cues about cells during migration, differentiation, and regeneration in the CNS environment.8 In addition, cells injected into the CSF may lack cell–cell contact and RGD signaling. Indeed, it has been shown that RGD signaling provided as part of the biomaterial system improves cell survival and function.23 The quality of hydrogels that is critical, with respect to their use in highly sensitive tissues of the CNS, is that they are biocompatible, minimizing adverse tissue reaction in vivo.24 Hydrogels can be easily tuned  in order to facilitate injectability. Their biomechanical properties can be adjusted for smooth flow with low resistance during infusion, as well as to broadly mimic the host microenvironment composition, including physical and mechanical characteristics representative of native CNS tissue, which minimizes mechanical mismatch.25With respect to application in the spinal cord, hydrogels are the system of choice to provide the appropriate mechanics for precise localization and spatio-temporal control of cell delivery, and that is particularly important in case of transplantation to the intrathecal space. The rationale for using injectable hydrogels for intrathecal stem cell delivery is based on the observations that stem cells transplanted into the CSF are subject to gravitational sedimentation.26 In fact, these types of gels often require a gelation-triggering system, such as local cooling,22 which introduces the risk of tissue damage, and, in case of intrathecal injection, is not applicable.Both physical and covalently cross-linked hydrogels have been applied to the treatment of spinal cord injury (SCI). Until now, only a few studies reported the development of injectable hydrogel systems for the intrathecal delivery of cells to the CSF. Physical gels are simpler to use, since they typically do not involve harsh cross-linking conditions, thus reducing the possible toxicity normally associated with the use of covalent coupling agents.27 Chemically cross-linked hyaluronan is an example where researchers exploited the biocompatible, biodegradable, angiogenic, and anti-inflammatory nature of the base polymer. For example, Gupta et al.28 described, for the first time, the physical blend of an HA and methyl cellulose (HAMC)-injectable hydrogel to deliver NSCs into the rat brain after a clip compression injury. Also, Mothe et al.29 examined the survival and efficacy of adult brain-derived neural stem/progenitor cells (NSPCs) injected within a modified HAMC hydrogel with recombinant rat platelet-derived growth factor-A (rPDGF-A). The authors showed that, while only a limited number of surviving cells was found, the hydrogel promoted the survival of host neurons and oligodendrocytes, which was associated with better functional recovery on the ladder walk.29 Further, the same authors reported that the modification of the previously used HAMC with RGD promoted the survival, integration, and differentiation of human pluripotent stem cell-derived oligodendrocyte progenitor cells30  hydrogels also showed a great potential to be used in cellular therapies designed to treat SCI. A co-culture of adipose stem cells (ASCs) and olfactory ensheathing cells (OECs) encapsulated into the GG-GRGDS hydrogel resulted in significant motor and histological improvements of SCI in rats.32Chemically cross-linked hydrogels, however, are relevant because they present more desirable properties than physical gels in terms of flexibility to manipulate physical and biological properties. Synthetic functional groups can be incorporated in the polymers to enable (or enhance) gelation, for improved in vivo stability, or to enhance specific enzymatic susceptibility of the hydrogels.In brief, the selection of biomaterials, the surface morphology of the substrates, neurotrophic factors, cell density, and the effect of serum and many other factors can all affect the proliferation and differentiation of cultured neural stem cells. When envisioning the design of the cell culture environment in vitro and in vivo, as many factors as possible related to biomaterials should be considered and optimized to achieve the best biological performance, in the short-term, medium-term, and long-term. All these studies provide a promising strategy, combining a biocompatible and injectable polymer and stem cells to form an effective cell transplantation system for the treatment of spinal cord diseases. In order to develop more efficient treatment solutions, future research should focus on optimizing the conditions for augmenting stem cell survival, proliferation, migration, differentiation, and integration into the host tissue.33 and it has been shown that the rheological properties of a given hydrogel vary.34 When a hydrogel is injected, its rheological behavior and viscoelastic properties  are negatively affected. In order to improve the viscoelastic properties, without altering the gel-like behavior of both acellular and cell-laden hydrogels, nanoparticles have been used as a reinforcement or filler material.35One of the most important characteristics of hydrogels that determine local microenvironment and injectability are their rheological properties36 The use of materials at the nanoscale provides the extraordinary possibility to modify some of the properties of therapeutic carriers, such as solubility, diffusivity, biodistribution, release characteristics, and immunogenicity. In addition, these kinds of carriers show a longer circulation half-life, superior bioavailability, and lower toxicity.38In fact, the use of nanoparticle-based systems has expanded interest because of the exciting prospects.40 There are different dendrimers that have been exploited extensively for drug delivery, including poly(amidoamine) (PAMAM), poly(etherhydroxylamine) (PEHAM), and poly(propyleneimine) (PPI) dendrimers.41 Because of their unique structures and properties, PAMAM dendrimers have been the most investigated for the use in CNS applications. In fact, Oliveira et al. reported a new functionalization for a PAMAM dendrimer, by grafting it to a carboxymethylchitosan (CMCht) to improve the loading capacity.42 That nanocarriers were shown to be internalized by primary neurons and glial cells in culture system, suggesting their utility for CNS indications39  for magnetic guidance of drugs and their targeted delivery.45 Lueshen et al.46 developed a physiologically and anatomically consistent in vitro human spine model that reproduced natural CSF pulsations to infused gold-coated magnetite nanoparticles. This system allowed a more targeted drug delivery to specific regions using an external magnetic field. The same authors proved the increase in targeting efficacy using magnetizable implants.47 More recently, they validated this intrathecal magnetic drug targeting (IT-MDT) approach in vivo using Sprague-Dawley rats.48Despite the large number of nanocarriers that are being developed and investigated for specific drug delivery purposes in the CNS, only a few studies have reported its application in the CSF. The vast majority of NPs for the CNS range from classical linear polymers to novel spherical molecules. For example, dendrimers that have a spherical morphology and highly branched have been shown to be interesting nanocarriers for CNS applications. They facilitate surface functionalization and control over their size, which influences the drug payload and targeting features.49 Minocycline-loaded PLGA nanoparticles showed no in vitro degradation of the drug in artificial CSF during the seven-day stability study.50With regard to the linear polymers, one of the most widely used for drug delivery is poly (PLGA), since it is biodegradable and there is minimal systemic toxicity associated with CNS applications.51 Meta-analyses of cell-mediated effects in preclinical cell therapy studies in neurological disorders have revealed the primary therapeutic mechanisms52 and nanotechnology can offer a non-invasive monitoring system for further improving these positive effects.In addition to the use of nanoparticles for drug or growth factor delivery systems, nanoparticles have gained special attention for stem cell tracking, namely, MNPs for detection by MRI. Cell tracking is important, as it allows for a better understanding and optimization of cell-mediated effects.53 in case of injection into the fluid compartments uncertainty is high. This uncertainty is related to the mixing and dilution of biomaterial with CSF and its redistribution with fluid circulation. In this context, it is highly desirable to monitor injected biomaterials using non-invasive imaging. Even though literature on image-guided intrathecal injection of biomaterial/cell composites is very limited, application of this approach in other organ systems is quite abundant thus here we will focus on the rationale and the needs of imaging for intrathecal injection, and, will suggest imaging strategies that are best suited to fulfill these needs. There are three areas where imaging could assist in improving the success of intrathecal biomaterial/cell injection including monitoring the procedure of biomaterial injection in real-time, longitudinal assessment and finally, molecular imaging of the local microenvironment at the injection site  is sufficient to track hydrogel integrity and release of therapeutics within the injected organism.56 However, to monitor delivery into deep structures, such as intravascular or intra-organ injection, including the intrathecal space, tomographic techniques  are usually required.59 Each imaging modality has unique properties with advantages and disadvantages; here, we will review these features as they relate to placement of biomaterials in the intrathecal space.Imaging is expected to provide a breadth of information about the biomaterial itself, the embedded cells, and the graft-tissue interactions in the context of the healing process. Moreover, it is important that imaging requirements, such as incorporation of the contrast agent, does not alter the properties of the biomaterial, does not interfere with biology of embedded cells, and, ideally, does not compromise functional assessment by any imaging modalities.60 Infusion of drugs as fluid suspension can be performed without complications even chronically over weeks or months, as they simply mix with the CSF. Implantation of hydrogels, however, is more demanding and requires more careful approach as it is desired that the material would persist locally in a specific and selected area of the intrathecal space over the required period of time. When biomaterial is being injected, dynamic imaging can be used to assure the precision of targeting and to minimize the risk of excessive injection or misplacement. Indeed, misplacement of the biomaterial may have negative consequences beyond the suboptimal therapeutic effect, as misinjected graft could lead to unwanted adverse effects. Infusion into intrathecal space results in its rostral or caudal spread from the catheter tip, or combination of the two. Without imaging in real-time, proper placement is practically impossible. Monitoring biomaterial biodistribution can be accomplished with the use of X-ray. X-ray imaging based on phase contrast proved to be capable of detecting the hydrogel structure without the addition of contrast agent. The nonporous and porous PEG hydrogels were discernible from surrounding water or soft tissue in vitro without the use of contrast agents.61 In addition, Faraj et al.62 demonstrated that high-resolution computed tomography (micro-CT) enables the determination of the structure of soft scaffolds in vitro. In addition to low X-ray attenuation of collagen-based hydrogels, different combinations of contrast agents were used. It was shown that the application of osmium tetroxide and uranyl acetate, or a combination of uranyl acetate and lead citrate, allowed high-resolution 3D imaging of the structure of the scaffolds. Lei et al.63 showed the possibility of non-invasive tracking of radiopaque thermo-reversible hydrogels after implantation, and the opportunity to obtain detailed 3D morphological information in a real-time manner. Due to its accessibility and low cost, X-ray imaging techniques are promising tools for hydrogel observation but ionizing radiation is a concern and the motivation for developing other imaging modalities such as MRI. Indeed MRI is extensively used in biomedicine64 and recently significant progress has been made in interventional MRI including real-time assessment of injected cells65 and biomaterials.66 MRI has many features that make it one of the most desirable and preferable imaging modalities for imaging in biomedicine. These features include excellent soft tissue contrast, tomographic capabilities, excellent anatomical information, and it is non-invasive and radiation-free. MRI has been widely used for in vivo and ex vivo analysis of biomaterials and transplanted cells, and, while detection of native components of hydrogel has been demonstrated,67 labeling with MRI contrast agent is usually required. Imaging moiety is often introduced in the form of a nanoparticle such as iron oxide68 gadolinium70 or fluorine nanoemulsions.71 Various types of nanocarriers have been developed including more advanced systems with both therapeutic and diagnostic components (Theranostic agents). Good example of such theranostic agents in the contex of regenerative medicine are iron oxide-based particles loaded with microRNAs for simultaneous tracking and manipulation of transplanted cells.72 Another application of nanoparticles for imaging is by combining contrast mechanism for more than one modality known as multimodality nanoparticles, such as a combination of PET, near-infrared fluorescence, and MRI73 While there are no published reports on intrathecal injection of biomaterials guided by dynamic imaging we would like to review several relevant applications based on imaging of labeled stem cells.Placement of the intrathecal catheter at the desired level of the spinal cord is performed under fluoroscopic visualization and this procedure is routinely performed clinically with an example of baclofen pump implantation for treatment of dystonia.74 Bigini et al.75 labeled human fetal cells with SPIO nanoparticles in the brain of mice with motor neuron disease. It was reported that transplanted cells rapidly diffused throughout the fourth ventricle at the level of the spinal cord, and the labeling did not affect the proliferation and metabolic activity of cells.75 MRI has been successfully used for the dynamic assessment of cell biodistribution in real-time during intra-arterial injection in rodents76 where imaging was instrumental in optimizing the procedure of cell delivery. Recently, real-time MRI monitoring has been applied to predict and improve the precision of cell delivery into the brain in small-animal and large-animal models.2 While real-time assessment of intrathecal injection of the biomaterial with MRI has not been reported it is highly feasible and application of this technique would likely provide important clues on how to assure reproducibility, reliability and efficacy of intrathecal biomaterial/cell delivery.Superparamagnetic iron oxide nanoparticles (SPION) are of particular interest for stem cell tracking, since they, in general, do not result in adverse effects on cell survival and functionality in terms of differentiation capacity, gene expression profiles, or migratory capacity.77 Nevertheless both X-ray and MRI has been used for monitoring injected biomaterials over time. One example is a study by Appel et al.78 showing that X-ray phase contrast (XPC) CT application allows 3D visualization and quantification of hydrated soft tissues and PEG hydrogels in vivo, with no contrast agents. The XPC CT imaging enabled a clear distinction between surrounding tissue after transplantation and the hydrogel structure. Also, tantalum, known for its biological properties of facilitating soft tissue regeneration and vascularization, is, at the same time a promising contrast agent for X-ray imaging, enhancing the visibility of cells and biomaterial grafts.79 MRI has been shown instrumental in the assessment of biomaterials biodegradability in a study reported by Yang et al..80 That work showed that the biodegradability level of hydrogels can be monitored and quantified in vivo using an alteration of 19F intensity. Recently, MR imaging of hydrogels transplanted as scaffolds, as well as an injectable formulation, has been reported.81 Zhang et al.82 presented in situ, cross-linkable, HA-based hydrogels, hybridized with iron oxide nanoparticles to enable their detection on MRI. Another interesting study used iron oxide as a contrast agent and multiple crystals of iron oxide were encapsulated inside the polyacrylamide matrix, yielding very high relaxivity. Because of the monitoring of the amount of liberated iron oxide nanoparticles by the hyaluronidases, it was possible to monitor and analyze the hydrogel degradation.83 Bible and co-workers84 showed non-invasive imaging of the ECM scaffold in a stroke-damaged rat brain using 19F MRI, demonstrating that transplantation of neural stem cells embedded in xenogeneic ECM scaffolds resulted in uniformly distributed cells throughout the lesion cavity.While most of the requirements for imaging of biomaterials over time are common with described above real-time imaging, there are few unique challenges related to specificity. The advantage of interventional imaging is an access to pre-injection baseline and unequivocal interpretation of post injection images following simple subtraction process. Longitudinal imaging introduces uncertainty as some pathological processes may imitate signal features of the graft with an example of hypointense signal produced by both iron oxide nanoparticle-based contrast agents and a hemorrhage.85 Endogenous molecules dependent on the content of labile protons in the sample may generate CEST contrast, thus facilitating their detection by CEST-MRI without any additional contrast agent. Liang et al.67 reported on the use of CEST-MRI to monitor biodegradation of a gelatin-containing HA-based hydrogels, both in vitro as well as in vivo in mice. In addition, Jin et al.86 described the use of CEST for both in vitro and in vivo examination of ECM hydrogels in a rat stroke model. In vitro CEST imaging was instrumental in demonstrating dynamic changes in the different components of the ECM inside the hydrogel. Moreover, in vivo CEST examination allowed detection of ECM hydrogel distribution and degradation that strongly corresponded to histological studies post mortem.86 Chan et al.57 described pH nanosensor-based magnetic resonance imaging as a modality with which to image encapsulated cell death in vivo. Ultrapure, low-viscosity, high-guluronate alginate and ultrapure, low-viscosity, high-mannuronate alginate (NovaMatrix), and liposomes containing l-arginine, were used for microcapsule preparation , which is a novel molecular MRI technique with the important advantage that components which naturally occur in the biomaterials are used to generate contrast.ion Fig. . It was 87GFP/Luc hMSCs were embedded in  alginate or in (SeaPlaque) agarose hydrogels and injected subcutaneously in rats. Although both hydrogel types showed a linear correlation between the BLI signal and the live cell number using a 30-min imaging protocol, there was a difference in the magnitude of the BLI signal measured between the agarose and alginate materials, exemplifying the utility of BLI for monitoring interactions between biomaterials and embedded cells. In addition, Liang et al. showed that BLI is useful for monitoring the viability of cells embedded in injectable hydrogel.88 That study showed that HA-based hydrogels improved the survival and proliferation of three different transplanted cell lines . Similarly, Levit et al. used Luc hMSCs encapsulated in a low-viscosity guluronic acid-based alginate  in a rat myocardial infarction model.89 BLI showed that encapsulation of MSCs in an LVG hydrogel minimized scar formation and improved cardiac function. Similarly, luciferase-expressing ASCs (Luc ASCs) embedded within fibrin scaffolds and transplanted in the injured heart were tracked with BLI as reported by Yang et al.90In the context of monitoring local cellular microenvironment it is important to mention bioluminescence imaging (BLI). This technique is based on a reporter gene  that is expressed by the cells of interest. As the photon signal is generated only by metabolically active cells and is dependent on access to ATP, it is an excellent method for in vivo monitoring of cell viability. Even though this modality is only applicable to small-animal models it is invaluable for assessment of biomaterial/cell composites. As described by Allen et al.Overall, several imaging modalities offer unique opportunities for non-invasive monitoring of the intrathecal injection. Each of the modalities has strengths and limitations with multimodality approach likely required for providing most comprehensive information.The spinal cord is clearly one of the most difficult targets for the transplantation of stem cells and one of the most challenging elements is the route of cell delivery. Diseases characterized by disseminated pathology require global cell engraftment, and, in these cases, intrathecal injection seems to be highly recommended. The infusion of cell suspensions directly into the CSF can result in cell sedimentation and suboptimal cell biodistribution, and hence, the need for supporting biomaterials. The transplantation of cells embedded in injectable hydrogels addresses the problem of possible cell sedimentation while mimicking the native extracellular matrix, additional benefits of hydrogels include bioadhesiveness and offer the potential for supplementation with nanocarriers laden with molecules that can promote survival and differentiation of stem cells. Finally, imaging technology offers unique opportunities for the characterization of cell-biomaterial composites both in vitro and after transplantation.As shown above, there have been several reports that advocate the use of the intrathecal route for stem cell delivery, and progress in the field of biomaterials is unprecedented, offering a breadth of injectable hydrogel materials that meet the requirements of intrathecal injection. While the applications for hydrogel-embedded stem cells for intrathecal transplantation are limited, we certainly hope this review will spark more interest in this exciting area. Recent progress in the non-invasive imaging of biomaterials, and, particularly, clinically applicable modalities, such as MRI, will help guide the development of more effective and safer protocols for intrathecal therapeutic cell transplantation.